Crystalline forms of a BTK inhibitor

Abstract

N-(3-(6-胺基-5-(2-(;N-甲基丙烯醯胺基)乙氧基)嘧啶-4-基)-5-氟-2-甲基苯基)-4-環丙基-2-氟苯甲醯胺的多種無水結晶形狀、及其組成物、製備方法和使用方法。這些結晶形狀可用於治療典型地藉由抑制BTK而改善的疾病和障礙。此類疾病和障礙可以包括炎症和自體免疫疾病以及肺和呼吸道炎症。;

Description

Technical Field

[0001] This disclosure relates to the crystalline form of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. This disclosure also relates to pharmaceutical compositions comprising such crystalline forms, methods for obtaining such crystalline forms, and methods for using such crystalline forms in the treatment of diseases and disorders typically improved by inhibiting Bruton's tyrosine kinase. Such diseases and disorders may include inflammatory and autoimmune diseases, as well as inflammation of the lungs and respiratory tract. Prior Technology

[0002] Polymorphism refers to the existence of more than one crystalline shape of a substance.

[0003] The solid form of the active pharmaceutical ingredient (API) of a particular drug is often a crucial determinant of its ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in vivo. Where the same constituent material crystallizes in different lattice arrangements, crystal shapes appear, leading to different thermodynamic properties and stability specific to a particular crystal shape. Crystal shapes can also include different hydrates or solvates of the same compound. In determining which form is preferred, many properties of the forms are compared, and the preferred form is selected based on many physical property variables. It is entirely possible that in some cases, where certain aspects such as ease of preparation and stability are considered crucial, one form may be preferred. In other cases, different forms may be preferred for greater dissolution rates and / or superior bioavailability.

[0004] Therefore, the ability of chemical substances to crystallize in more than one crystalline form can profoundly influence a drug's shelf life, solubility, formulation characteristics, and processing properties. Furthermore, drug efficacy can be affected by drug molecular polymorphism. Different polymorphs can have different uptake rates in vivo, resulting in lower or higher biological activity than desired. In extreme cases, undesirable polymorphs may even exhibit toxicity. The occurrence of unknown crystalline forms during manufacturing can also have significant implications.

[0005] It is not yet possible to predict whether a particular compound or its salt will form a polymorph, whether any such polymorph will be suitable for commercial use in a therapeutic composition, or which polymorph will exhibit such desirable properties. However, in some cases, knowing which crystal systems a drug may have allows researchers to maximize the desired properties of a compound, such as solubility, formulation properties, processing characteristics, and shelf life. Understanding these factors early in new drug development may mean more active, more stable, or cheaper drugs.

[0006] Therefore, there is a need to provide N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide in solid form, which has physicochemical properties that allow for the reliable and safe production of an effective pharmaceutical product containing N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide.

[0007] N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide in Example 6 was first disclosed in WO 2015 / 079417, filed November 28, 2014, which is incorporated herein by reference in its entirety. N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide is a Bruton's tyrosine kinase (BTK) inhibitor having the structure of formula (I): [Mode] [(I)]

[0008] However, WO 2015 / 079417 does not provide information on the crystalline form of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. The crystalline form of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide has been discovered, and it can be used to treat diseases typically improved by inhibiting BTK. Such diseases and conditions include inflammatory and autoimmune diseases, as well as inflammation of the lungs and respiratory tract. Summary of the Invention

[0009] In one aspect, the present invention provides three crystalline forms of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine in a free form (i.e., a non-salt form). In a specific embodiment, these free forms are anhydrous forms of compounds having formula (I).

[0010] These crystalline forms include those designated herein as types A, B, and C. The names used herein to identify specific forms (e.g., "type A," "type B," or "type C") should not be considered as limitations on any other substance having similar or identical physical and chemical characteristics, but rather should be understood as identifiers to be interpreted solely based on the characteristic information also presented herein.

[0011] In one aspect, the present invention also provides a pharmaceutical composition comprising: (a) a therapeutically effective amount of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine in crystalline form A; and (b) at least one pharmaceutically acceptable carrier. Preferably, crystalline form A is substantially pure. More preferably, form A is substantially homogeneous.

[0012] In one aspect, the present invention also provides a pharmaceutical composition comprising: (a) a therapeutically effective amount of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine in crystalline form B; and (b) at least one pharmaceutically acceptable carrier. Preferably, crystalline form B is substantially pure. More preferably, form B is substantially homogeneous.

[0013] In one aspect, the present invention also provides a method for preparing crystalline form A of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, the method comprising the following steps: a) Reaction of N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide and acrylic anhydride in a non-chlorinated solvent, or, if necessary, in the presence of an inorganic base; and b) Separation into a solid crystalline form A (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

[0014] In one aspect, the present invention also provides a method for treating disorders mediated by BTK or disorders improved by inhibiting BTK, the method comprising administering to a patient requiring such treatment a therapeutically effective amount of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine in crystalline form A. Preferably, crystalline form A is substantially homogeneous.

[0015] In one aspect, the present invention also provides a method for treating disorders mediated by BTK or improved by inhibiting BTK, the method comprising administering to a patient requiring such treatment an effective amount of substantially pure crystalline form B of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. Preferably, crystalline form B is substantially pure.

[0016] In one aspect, the present invention also provides the use of crystalline form A of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine for the preparation of a medicament for treating disorders mediated by BTK or improved by inhibiting BTK. Preferably, crystalline form A is substantially homogeneous.

[0017] In one aspect, the present invention also provides the use of substantially pure crystalline form B of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine for the preparation of a medicament for treating disorders mediated by BTK or improved by inhibiting BTK. Preferably, crystalline form B is substantially pure.

[0018] In one aspect, the present invention also provides crystalline form A of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide for use in the treatment of disorders mediated by BTK or disorders improved by inhibiting BTK. Preferably, crystalline form A is substantially homogeneous.

[0019] In one aspect, the present invention also provides a substantially pure crystalline form B of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide for use in the treatment of disorders mediated by BTK or improved by inhibiting BTK. Preferably, crystalline form B is substantially pure.

[0020] Therefore, the crystalline form of compounds having formula (I) as described herein can be used to treat the following diseases or disorders mediated by or improved by BTK inhibition: autoimmune diseases, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases in which antibody production, antigen presentation, cellular mediator production, or lymphoid organogenesis are abnormal or undesirable; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura. Purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombocytopenic purpura, chronic urticaria (chronic spontaneous urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease (Morbus syndrome) Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism; hematopoietic cancers, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenstrom's disease. []

[0021] The crystalline form of compounds having formula (I) is particularly useful in the treatment of rheumatoid arthritis; chronic urticaria, preferably chronic spontaneous urticaria; Sjögren's syndrome, multiple sclerosis, atopic dermatitis or asthma. Simple Explanation of the Diagram

[0022] [ [picture] [1] provides an illustrative XRPD spectrum of the anhydrous crystal form (designated as type A herein) of the compound having formula (I), showing the 2θ (2-θ) degree on the X-axis and the relative intensity on the Y-axis.

[0023] [ [picture] [2] provides an illustrative DSC of the anhydrous crystalline shape (designated as type A herein) of compounds having formula (I).

[0024] [ [picture] [3] provides an illustrative TGA of the anhydrous crystalline forms of compounds having formula (I) (designated herein as type A).

[0025] [ [picture] [4] provides an illustrative XRPD spectrum of the anhydrous crystal form (designated as type B herein) of the compound having formula (I), showing the 2θ (2-θ) degree on the X-axis and the relative intensity on the Y-axis.

[0026] [ [picture] [5] provides an illustrative DSC of the anhydrous crystalline shape of compounds having formula (I) (designated herein as type B).

[0027] [ [picture] [6] provides an illustrative TGA of the anhydrous crystalline forms of compounds having formula (I) (designated herein as type B).

[0028] [ [picture] [7] provides an illustrative XRPD spectrum of the anhydrous crystal form (designated as type C herein) of the compound having formula (I), showing the 2θ (2-θ) degree on the X-axis and the relative intensity on the Y-axis.

[0029] [ [picture] [8] provides an illustrative DSC of the anhydrous crystalline shape (designated as type C herein) of compounds having formula (I).

[0030] [ [picture] [9] provides an illustrative TGA of the anhydrous crystalline forms (designated as type C herein) of compounds having formula (I).

[0031] Tables 1 and 2 below provide a more detailed list of XRPD peaks for each of types A, B, and C, respectively, along with the relative intensity % (I / I0 x 100). It should be understood that inherent variability exists in values ​​measured at 2θ degrees (°2θ) in X-ray powder diffraction spectra or X-ray powder diffraction diagrams due to, for example, instrument variations (including differences between instruments). Similarly, it should be understood that there is a variability of up to ±0.2 °2θ in XRPD peak measurements; however, such peaks will still be considered representative of the specific solid-state form of the crystalline material described herein. It should also be understood that other measurements from XRPD and DSC / TGA experiments (such as relative intensity and water content) may vary due to, for example, sample preparation and / or storage and / or environmental conditions; however, such measurements will still be considered representative of the specific solid-state form of the crystalline material described herein. Implementation

[0032] [definition] [] As used herein, the terms “about” and “substantially” indicate that their values ​​can vary for characteristics such as endothermic, endothermic peaks, exothermic, baseline shifts, etc. Regarding X-ray diffraction peak positions, “about” or “substantially” means taking into account typical peak position and intensity variability. For example, those skilled in the art will understand that peak position (2θ) can show variability between some apparatuses, typically up to 0.2°. Occasionally, variability may be greater than 0.2°, depending on differences in apparatus calibration. Furthermore, those skilled in the art will understand that relative peak intensities will show variability between apparatuses as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be used only as qualitative measurements. For DSC, the observed temperature changes will depend on the rate of temperature change and the sample preparation technique and the specific instrument used. Therefore, the endothermic / melting point values ​​reported herein for DSC / TGA thermal analysis plots can vary by ±5°C (and are still considered characteristic of the specific crystalline shape described herein). When used in the context of other characteristics such as weight percentage (by weight %) or reaction temperature, the term "about" indicates a variance of ± 5%.

[0033] The terms "one or more crystalline shapes," "one or more crystalline variants," "one or more polymorphs," or "one or more polymorphs" will be used interchangeably herein. As used herein, "polymorph" refers to a crystal form having the same chemical composition but with different spatial arrangements of the molecules, atoms, and / or ions that form the crystal. Each polymorph differs in thermodynamic stability, physical parameters, X-ray structure, and preparation method.

[0034] As used herein, "amorphous" refers to a solid form that is not a crystal, consisting of molecules, atoms, and / or ions. Amorphous solids do not exhibit defined X-ray diffraction patterns.

[0035] As used herein, when referring to a form, "substantially pure" means a compound having a purity greater than 90% by weight, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, and also includes a purity of approximately 100% by weight of a compound having formula (I). The remaining material comprises one or more other forms of the compound, and / or reactive impurities and / or processing impurities arising from its preparation. For example, the crystalline form of a compound having formula (I) can be considered substantially pure because it has a purity greater than 90% by weight as measured by means known and generally accepted in the art at this time, wherein the remaining less than 10% by weight of the material comprises one or more other forms of the compound having formula (I) and / or reactive impurities and / or processing impurities.

[0036] As used herein, when referring to any crystalline form of a compound having formula (I), "substantially phase-pure" means a compound having a phase purity of more than about 90% by weight based on the weight of the compound (on anhydrous basis), including more than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and about 99% by weight, and also including a phase purity of about 100% by weight of a compound having formula (I). The terms "phase-pure" or "phase purity" herein refer to the phase homogeneity of a particular solid form of a compound having formula (I) and do not necessarily imply a high degree of chemical purity in the absence of an explicit statement thereof. Phase purity can be determined by methods known in the art, for example, by quantitative phase analysis using XRPD with one or more methods known in the art, for example by external standard method, direct comparison of line (peak) characteristics (attributed to different phases in a particular spectrum), or by internal standard method. However, the presence of amorphous materials can complicate XRPD quantification of phase purity. Therefore, other methods that can be used to determine phase purity include, for example, solid-state NMR spectroscopy, Raman spectroscopy, and / or infrared spectroscopy. Those skilled in the art will readily understand these methods and how to employ these additional (or alternative) methods to determine phase purity.

[0037] As used herein, when referring to any crystalline form of a compound having formula (I), "substantially chemically pure" means a compound having a chemical purity of more than about 90% by weight based on the weight of the compound (on anhydrous basis), including more than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and about 99% by weight, and also including a chemical purity of about 100% by weight of a compound having formula (I). The remaining material typically includes other compounds (e.g., other stereoisomers of compounds having formula (I), reaction impurities, starting materials, reagents, byproducts, and / or other processing impurities arising from the preparation and / or isolation and / or purification of a particular crystalline form. For example, if a compound having formula (I) has been determined to have a crystalline shape with a chemical purity greater than about 90% by weight, as measured by methods known in the art and generally accepted, it can be considered substantially chemically pure, wherein the remaining less than about 10% by weight constitutes other materials, such as other stereoisomers of the compound having formula (I), reaction impurities, starting materials, reagents, byproducts, and / or processing impurities. Chemical purity can be determined according to methods known in the art, such as high-performance liquid chromatography (HPLC), LC-MS (liquid chromatography-mass spectrometry), nuclear magnetic resonance (NMR) spectroscopy, or infrared spectroscopy. Those skilled in the art will readily understand these methods and how to use these additional (or alternative) methods to determine chemical purity.

[0038] As used herein, the term "seed" can be used as a noun to describe one or more crystals of a crystalline compound having formula (I). The term "seed" can also be used as a verb to describe the act of introducing one or more crystals of the crystalline compound having formula (I) into an environment (including, but not limited to, a solution, mixture, suspension, or dispersion) resulting in the formation of more crystals of the crystalline compound having formula (I) or the growth of introduced crystals of the crystalline compound having formula (I).

[0039] The term "therapeuticly effective amount" for the compounds of this invention refers to the amount of the compound of this invention that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or relief of symptoms, symptom relief, slowing or delaying disease progression, or prevention of disease, etc.). In one non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of this invention that, when administered to a subject, effectively (1) at least partially relieves, inhibits, prevents, and / or improves (i) a symptom, disorder, or disease mediated by BTK, or (ii) related to BTK activity, or (iii) characterized by BTK activity (normal or abnormal); or (2) reduces or inhibits BTK activity; or (3) reduces or inhibits BTK expression. In another non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of this invention that, when administered to cells, or tissues, or non-cellular biological materials, or media, effectively reduces or inhibits BTK activity at least partially; or partially or completely reduces or inhibits BTK expression.

[0040] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. Subjects include, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the subject is a human.

[0041] As used in this article, a subject is considered "needing" or "in need of" treatment if the subject will benefit from the treatment biologically, medically, or in terms of quality of life.

[0042] As used herein, unless otherwise indicated herein or clearly contradicted by the context, the terms "a / an", "the", and similar terms used in the context of this invention (particularly in the context of the claims) shall be construed as encompassing both the singular and plural forms.

[0043] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. Any and all instances or exemplary language (e.g., "as") used herein are intended only to better illustrate the invention and not to limit the scope of the otherwise claimed invention.

[0044] As used herein, the term "inhibit (inhibition or inhibiting)" means the reduction or suppression of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0045] As used herein, the term "treat, treating, or treatment" for any disease or disorder, in one embodiment, means improving the disease or disorder (i.e., slowing down, stopping, or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat, treating, or treatment" means improving or alleviating at least one bodily parameter, including those that cannot be identified by the patient. In yet another embodiment, "treat, treating, or treatment" means regulating the disease or disorder physically (e.g., stabilization of identifiable symptoms), physiologically (e.g., stabilization of bodily parameters), or both. In one embodiment, "treat or treating" means delaying the progression of the disease or disorder.

[0046] As used herein, the term "preventing" for any disease or disorder refers to preventive treatment of the disease or disorder, or delaying the onset of the disease or disorder.

[0047] The term "comprising" encompasses both "including" and "consisting of"; for example, a composition that includes X may consist of only X, or may include others, such as X and Y.

[0048] As used herein, the term "combination" refers to a fixed combination, or combination dosing, of a dosage unit, wherein the crystalline form of a compound having formula (I) and the combination partner (i.e., an immunotherapeutic agent) can be administered independently at the same time or separately at time intervals, particularly where these time intervals allow the combination partner to exhibit synergy, such as a co-existing effect. Individual components may be packaged in a kit or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to dosing.

[0049] As used herein, the terms “co-administration” or “combination administration” mean to administer a selected combination of drugs to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the drugs are not necessarily administered via the same route of administration or administered simultaneously.

[0050] As used herein, the terms "drug combination" and "combination product" are used interchangeably and refer to a fixed combination in the form of a single dose unit or a non-fixed combination or kit for combined administration, wherein two or more therapeutic agents may be administered independently at the same time or separately at time intervals, particularly where these time intervals allow the combination couple to exhibit synergy, such as a co-existing effect. The term "fixed combination" means the crystalline form of a compound of formula (I) and the combination couple (i.e., an immunotherapeutic agent), administered simultaneously to a patient as a single entity or dose. The term "non-fixed combination" means the crystalline form of a compound of formula (I) and the combination couple (i.e., an immunotherapeutic agent), administered simultaneously, in parallel, or sequentially to a patient as separate entities (without a specific time limit), wherein such administration provides a therapeutically effective level of the two compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more therapeutic agents. In a preferred embodiment, the drug combination is a non-fixed combination.

[0051] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat BTK-related diseases as described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as administration in a single capsule containing the active ingredients in a fixed ratio. Alternatively, such administration may encompass co-administration in multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration also encompasses the sequential use of each type of therapeutic agent at substantially the same time or at different times. In any case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the condition or disorder described herein. [Crystal shape:] []

[0052] This disclosure describes and characterizes the anhydrous crystalline form of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide (a compound having formula (I)).

[0053] In one embodiment, this disclosure provides the crystalline form (type A) of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine, having an X-ray powder diffraction (XRPD) pattern containing a representative peak at 23.9 ± 0.2 °2θ, measured at a temperature of about 25°C. In another embodiment, the XRPD pattern further includes one or more additional representative peaks selected from 15.6 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, and 23.4 ± 0.2 °2θ. In one aspect of the foregoing embodiments, the XRPD plot further includes measurements taken at approximately 25°C of one or more additional representative peaks selected from 7.8 ± 0.2 °2θ, 13.6 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, and 29.6 ± 0.2 °2θ. In another aspect of the foregoing embodiments, the XRPD plot of the crystalline shape A of the compound having formula (I) may further include measurements taken at approximately 25°C of one, two, three, or four representative peaks selected from 9.2 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 25.2 ± 0.2 °2θ, and 29.6 ± 0.2 °2θ. Therefore, the XRPD plot of the crystalline shape A of the compound having formula (I) can be measured at a temperature of about 25°C, selected from 7.8 ± 0.2 °2θ, 9.2 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 13.6 ± 0.2 °2θ, 15.6 ± 0.2 °2θ, 16.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 22.1 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, 23.9 ± 0.2 °2θ, 24.8 ± 0.2 °2θ, 25.2 ± 0.2 °2θ, 25.5 ± 0.2 °2θ. One or more representative peaks of °2θ, 27.2 ± 0.2 °2θ, and 29.6 ± 0.2 °2θ. The XRPD plot of crystal shape A may contain one or more (e.g., two, three, four, five, or six) representative peaks selected from those disclosed in Table 1 and measured at a temperature of about 25°C.

[0054] In another aspect of the above embodiments, the crystalline shape A of the compound having formula (I) is characterized by the following X-ray powder diffraction pattern, which comprises four or more 2θ values ​​(CuKα λ = 1.54184 Å) selected from the group consisting of: 7.8 ± 0.2 °2θ, 9.2 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 13.6 ± 0.2 °2θ, 15.6 ± 0.2 °2θ, 16.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 22.1 ± 0.2 °2θ, 23.4 ± 0.2 °2θ. °2θ, 23.9 ± 0.2 °2θ, 24.8 ± 0.2 °2θ, 25.2 ± 0.2 °2θ, 25.5 ± 0.2 °2θ, 27.2± 0.2 °2θ, and 29.6 ± 0.2 °2θ. In another aspect of the above embodiments, the crystalline shape A of the compound having formula (I) is characterized by the following X-ray powder diffraction pattern, which comprises five or more 2θ values ​​(CuKα λ = 1.54184 Å) selected from the group consisting of: 7.8 ± 0.2 °2θ, 9.2 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 13.6 ± 0.2 °2θ, 15.6 ± 0.2 °2θ, 16.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 22.1 ± 0.2 °2θ, 23.4 ± 0.2 °2θ. °2θ, 23.9 ± 0.2 °2θ, 24.8 ± 0.2 °2θ, 25.2 ± 0.2 °2θ, 25.5 ± 0.2 °2θ, 27.2± 0.2 °2θ, and 29.6 ± 0.2 °2θ.

[0055] In another aspect of the above embodiments, the crystalline shape A of the compound having formula (I) has an XRPD diagram that is substantially as shown in Figure 1.

[0056] The crystalline form A of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine can be thermally characterized. In one embodiment, by differential scanning calorimetry (DSC) at a heating rate of 10°C / min, the crystalline form A of the compound having formula (I) has the following thermal profile, which includes a single endothermic peak starting at approximately 194°C (corresponding to melting).

[0057] In another embodiment, the crystalline shape A of the compound having formula (I) has a DSC thermal analysis pattern substantially as shown in Figure 2. It should be understood that the hydration form depends on the instrument parameters and can produce different thermal analysis patterns (in terms of peak shape and profile), so the same material can have thermal analysis patterns that appear substantially different from each other when data are generated on two different instruments.

[0058] In another embodiment, the crystalline shape A of the compound having formula (I) has a thermogravimetric analysis (TGA) plot that is substantially the same as that shown in Figure 3. The TGA weight loss is approximately 0.3% in the range of 40°C–200°C. Thermal decomposition occurs at 240°C.

[0059] In yet another embodiment, the crystal form of the A-series is substantially pure.

[0060] In yet another embodiment, the crystal form of the A series is substantially chemically pure.

[0061] In yet another embodiment, the crystal shapes of the A-system are substantially homogeneous.

[0062] In one embodiment, the present invention relates to a method for preparing crystalline form A of compound N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, the method comprising the following steps: a) Reaction of N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide and acrylic anhydride in a non-chlorinated solvent, or, if necessary, in the presence of an inorganic base; and b) Separation into a solid crystalline form A (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

[0063] In another embodiment, the present invention relates to a method for preparing crystalline form A of compound N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine, the method comprising the following steps: (a) Reaction of N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide and acrylic anhydride in a non-chlorinated solvent, or, if necessary, in the presence of a base; (b) Add water to quench the reaction to form an aqueous and organic phase; (c) Separation of the organic phase; (d) Wash the organic phase with an acid solution; and (e) Separation into a solid crystalline form A (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

[0064] In one aspect of the two aforementioned embodiments, step (a) of the method is performed at a temperature of about 20°C to about 65°C. Preferably, step (a) is performed at a temperature of about 40°C to about 65°C, and most preferably, at a temperature of about 50°C.

[0065] In another aspect of the three aforementioned embodiments, step (a) of the method is carried out in a non-chlorinated solvent selected from ethyl acetate and isopropyl acetate, preferably ethyl acetate.

[0066] In another aspect of the aforementioned four embodiments, step (a) is carried out in the presence of an inorganic base, preferably a carbonate base, and more preferably sodium carbonate.

[0067] In another aspect of the aforementioned five embodiments, the method further includes a step following step (b) but preceding step (c), which consists of stirring and heating the reaction mixture to a temperature of approximately 50°C to approximately 65°C, and cooling it to room temperature prior to step (c). This additional step can be used to more effectively remove acrylic acid byproducts.

[0068] In another aspect of the aforementioned six embodiments, the acid solution used in step (d) has a pH of approximately 1. For example, the acid solution is a sulfuric acid solution (e.g., 0.05 M). The organic phase is washed with the acid solution to remove the following byproducts from the reaction mixture: .

[0069] In another aspect of the aforementioned seven embodiments, type A is separated into a solid by antisolvent crystallization. The antisolvent is a solvent in which the compound having formula (I) has low solubility (e.g., solubility less than 0.5 mg / mL, preferably less than 0.25 mg / mL). Non-limiting examples of antisolvents used in this method are heptane, hexane, tributyl methyl ether, toluene, or acetonitrile.

[0070] In another preferred aspect of the aforementioned seven embodiments, type A is separated into solids by a distillation process.

[0071] The present invention also provides a method for preparing type A N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, the method comprising the following steps: (a) Suspending crystal form B of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, or crystal form C of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, or a mixture of types B and C, in a non-chlorinated solvent; and (b) And the A type is separated into solids (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

[0072] The present invention also provides a method for preparing type A N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, the method comprising the following steps: (a) Suspending crystal form B of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, or crystal form C of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, or a mixture of types B and C, in a non-chlorinated solvent; and (b) Allow the suspension to equilibrate at room temperature for at least 2 weeks, or allow it to equilibrate at 50°C for at least 1 week; and (c) Separation of type A as a solid (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

[0073] In one aspect of the two aforementioned embodiments, the non-chlorinated solvent is selected from 1,4-dichloroisocyanuric acid, alcohol, acetone, acetonitrile, tetrahydrofuran, water, pyridine, nitromethane, anisole, and alkyl acetate.

[0074] In another aspect of the aforementioned three embodiments, depending on the non-chlorinated solvent, crystalline form B or crystalline form C, or a mixture thereof, can be dissolved. In this case, the separation of form A as a solid can be achieved through antisolvent crystallization, cooling crystallization, distillation, or solvent evaporation. In other aspects, forms B, C, or mixtures thereof can remain in suspension, in which case form A is separated by filtration.

[0075] The present invention further provides a crystalline form (type B) of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine having an X-ray powder diffraction (XRPD) pattern containing a representative peak at 20.9 ± 0.2 °2θ, measured at a temperature of about 25°C. In another embodiment, the XRPD pattern further contains one or more additional representative peaks selected from 6.7 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 17.9 ± 0.2 °2θ, 20.2 ± 0.2 °2θ, 20.9 ± 0.2 °2θ, and 24.0 ± 0.2 °2θ, measured at a temperature of about 25°C. In one aspect of the aforementioned implementation scheme, the XRPD plot of crystal shape B may further include measurements taken at a temperature of approximately 25°C, selecting one, two, three, or four representative peaks from 5.9 ± 0.2 °2θ, 13.0 ± 0.2 °2θ, 14.8 ± 0.2 °2θ, 19.0 ± 0.2 °2θ, and 22.6 ± 0.2 °2θ.

[0076] Therefore, the XRPD diagram of crystal shape B can include values ​​selected from 5.9 ± 0.2 °2θ, 6.7 ± 0.2 °2θ, 7.8 ± 0.2 °2θ, 8.3 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 12.1 ± 0.2 °2θ, 12.6 ± 0.2 °2θ, 13.0 ± 0.2 °2θ, 13.3 ± 0.2 °2θ, 14.8 ± 0.2 °2θ, 15.8 ± 0.2 °2θ, 16.4 ± 0.2 °2θ, 17.6 ± 0.2 °2θ, 19.5 ± 0.2 °2θ, 20.2 ± 0.2 °2θ, 20.6 ± 0.2 °2θ, 20.9 ± 0.2 °2θ, and 21.6 ± 0.2 °2θ. The XRPD plot of crystal shape B may contain one or more (e.g., two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 2, as well as one or more (e.g., two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 2, measured at a temperature of approximately 25°C.

[0077] In another embodiment, the type B is characterized by an X-ray powder diffraction pattern comprising four or more 2θ values ​​(CuKα λ = 1.54184 Å) selected from the group consisting of: 5.9 ± 0.2 °2θ, 6.7 ± 0.2 °2θ, 7.8 ± 0.2 °2θ, 8.3 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 12.1 ± 0.2 °2θ, 12.6 ± 0.2 °2θ, 13.0 ± 0.2 °2θ, 13.3 ± 0.2 °2θ, 14.8 ± 0.2 °2θ, 15.8 ± 0.2 °2θ, 16.4 ± 0.2 °2θ, 17.6 ± 0.2 °2θ, and 19.5 ± 0.2 °2θ. °2θ, 20.2 ± 0.2 °2θ, 20.6 ± 0.2 °2θ, 20.9 ± 0.2 °2θ, 21.6 ± 0.2 °2θ, 22.3 ± 0.2 °2θ, 23.3± 0.2 °2θ, 24.0± 0.2 °2θ, 24.9 ± 0.2 °2θ, and 25.3± 0.2 °2θ.

[0078] In another embodiment, the type B is characterized by an X-ray powder diffraction pattern comprising five or more 2θ values ​​(CuKα λ = 1.54184 Å) selected from the group consisting of: 5.9 ± 0.2 °2θ, 6.7 ± 0.2 °2θ, 7.8 ± 0.2 °2θ, 8.3 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 12.1 ± 0.2 °2θ, 12.6 ± 0.2 °2θ, 13.0 ± 0.2 °2θ, 13.3 ± 0.2 °2θ, 14.8 ± 0.2 °2θ, 15.8 ± 0.2 °2θ, 16.4 ± 0.2 °2θ, 17.6 ± 0.2 °2θ, and 19.5 ± 0.2 °2θ. °2θ, 20.2 ± 0.2 °2θ, 20.6 ± 0.2 °2θ, 20.9 ± 0.2 °2θ, 21.6 ± 0.2 °2θ, 22.3 ± 0.2 °2θ, 23.3± 0.2 °2θ, 24.0± 0.2 °2θ, 24.9 ± 0.2 °2θ, and 25.3± 0.2 °2θ.

[0079] In yet another embodiment, the crystalline shape B of the compound having formula (I) has an XRPD diagram that is substantially as shown in Figure 4.

[0080] The crystalline form B of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine can be thermally characterized. In one embodiment, the crystalline form B of the compound having formula (I) has a differential thermogravimetric curve measured by DSC at a heating rate of 10°C / min, which includes an endothermic peak starting at about 170°C (corresponding to the melting of variant B), an exothermic peak starting at about 175°C (corresponding to recrystallization to variant A), and an endothermic peak starting at about 194°C (corresponding to the melting of variant A).

[0081] In another embodiment, the crystalline form B of the compound having formula (I) has a DSC thermal analysis pattern substantially as shown in Figure 5. It should be understood that the hydration form depends on the instrument parameters and can produce different thermal analysis patterns (in terms of peak shape and profile), so the same material can have thermal analysis patterns that appear substantially different from each other when data are generated on two different instruments.

[0082] In another embodiment, the crystalline shape B of the compound having formula (I) has a substantially identical thermogravimetric analysis (TGA) plot as shown in Figure 6. The TGA weight loss is approximately 0.2% in the range of 40°C–160°C. Thermal decomposition occurs above 240°C.

[0083] In yet another embodiment, the B-series crystals are substantially pure.

[0084] In yet another embodiment, the B-series crystals are substantially chemically pure.

[0085] In yet another embodiment, the crystal shapes of the B-system are substantially homogeneous.

[0086] In one embodiment, the present invention relates to a method for preparing crystalline form B of compound N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, said method comprising the following steps: (a) Suspension of type A in dichloromethane for approximately 3 days at a temperature of approximately 40°C; (b) Allow the suspension to equilibrate at room temperature for approximately 5 days; and (c) Separate the B type as a solid (e.g., by filtration).

[0087] In yet another embodiment, the present invention relates to a method for preparing crystalline form B of compound N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, said method comprising the following steps: a) Suspend variant A in a solvent mixture containing at least 50% dichloromethane by volume; b) Allow the suspension to equilibrate at approximately 50°C for about 2 weeks; c) Cool the suspension to room temperature; and d) Separating solids from a suspension (e.g., by filtration).

[0088] In one aspect of the above implementation scheme, the solvent mixture is MeOH / dichloromethane 50:50 (v / v).

[0089] The present invention further provides a crystalline form (type C) of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine having an X-ray powder diffraction (XRPD) pattern containing a representative peak at 5.9 ± 0.2 °2θ, measured at a temperature of about 25°C. In another embodiment, the XRPD pattern further contains one or more additional representative peaks selected from 11.9 ± 0.2 °2θ, 17.0 ± 0.2 °2θ, and 19.3 ± 0.2 °2θ, measured at a temperature of about 25°C. In one aspect of the aforementioned embodiment, the XRPD plot of crystal shape C may further include measurements taken at a temperature of approximately 25°C, selecting one, two, three, or four representative peaks from 12.5 ± 0.2 °2θ, 15.3 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.2 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, and 23.7 ± 0.2 °2θ.

[0090] Therefore, the XRPD diagram of crystal shape C can include values ​​selected from 5.9 ± 0.2 °2θ, 11.9 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 12.5 ± 0.2 °2θ, 12.9 ± 0.2 °2θ, 14.4 ± 0.2 °2θ, 14.6 ± 0.2 °2θ, 15.3 ± 0.2 °2θ, 17.0 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 19.0 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 20.2 ± 0.2 °2θ, 20.8 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.2 ± 0.2 °2θ, and 22.8 ± 0.2 °2θ. The XRPD plot of crystal shape C may include one or more (e.g., two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 3, as well as one or more (e.g., two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 3, measured at a temperature of approximately 25°C.

[0091] In another embodiment, the C-type is characterized by an X-ray powder diffraction pattern comprising four or more 2θ values ​​(CuKα λ = 1.54184 Å) selected from the group consisting of: 5.9 ± 0.2 °2θ, 11.9 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 12.5 ± 0.2 °2θ, 12.9 ± 0.2 °2θ, 14.4 ± 0.2 °2θ, 14.6 ± 0.2 °2θ, 15.3 ± 0.2 °2θ, 17.0 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 19.0 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 20.2 ± 0.2 °2θ. °2θ, 20.8 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.2 ± 0.2 °2θ, 22.8 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, 23.7± 0.2 °2θ, 25.3± 0.2 °2θ, 26.1 ± 0.2 °2θ, and 26.9± 0.2 °2θ.

[0092] In another embodiment, the C-type is characterized by an X-ray powder diffraction pattern comprising five or more 2θ values ​​(CuKα λ = 1.54184 Å) selected from the group consisting of: 5.9 ± 0.2 °2θ, 11.9 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 12.5 ± 0.2 °2θ, 12.9 ± 0.2 °2θ, 14.4 ± 0.2 °2θ, 14.6 ± 0.2 °2θ, 15.3 ± 0.2 °2θ, 17.0 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 19.0 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 20.2 ± 0.2 °2θ. °2θ, 20.8 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.2 ± 0.2 °2θ, 22.8 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, 23.7± 0.2 °2θ, 25.3± 0.2 °2θ, 26.1 ± 0.2 °2θ, and 26.9± 0.2 °2θ.

[0093] In yet another embodiment, the crystalline shape C of the compound having formula (I) has an XRPD diagram that is substantially as shown in Figure 7.

[0094] The crystalline form C of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine can be thermally characterized. In one embodiment, the crystalline form C of the compound having formula (I) has a differential thermogravimetric curve measured by DSC at a heating rate of 10°C / min, which includes a small exothermic peak between 90°C and 120°C (corresponding to the solid / solid transition from variant C to variant B), an endothermic peak starting at about 171°C (corresponding to the melting of variant B), an exothermic peak starting at about 175°C (corresponding to recrystallization to variant A), and an endothermic peak starting at about 195°C (corresponding to the melting of variant A).

[0095] In another embodiment, the crystalline shape C of the compound having formula (I) has a DSC thermal analysis pattern substantially as shown in Figure 8. It should be understood that the hydration form depends on the instrument parameters and can produce different thermal analysis patterns (in terms of peak shape and profile), so the same material can have thermal analysis patterns that appear substantially different from each other when data are generated on two different instruments.

[0096] In another embodiment, crystal shape C has a substantially identical thermogravimetric analysis (TGA) plot to that shown in Figure 9. The TGA weight loss is approximately 0.01% in the range of 40°C–150°C. Thermal decomposition occurs above 240°C.

[0097] In yet another embodiment, the crystalline shape of the C-system is substantially pure.

[0098] In yet another embodiment, the crystal shape is chemically pure according to the C-system.

[0099] In yet another embodiment, the crystalline shapes of the C-system are substantially homogeneous.

[0100] In one embodiment, the present invention relates to a method for preparing the crystalline form C of compound N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide, the method comprising the following steps: a) Progenitor A was suspended in dichloromethane at a temperature of approximately 40°C for about 3 days; b) Cool the suspension to room temperature; c) Separate C-type components that are in solid form (e.g., by filtration).

[0101] In another embodiment, the present invention relates to a method for preparing the crystalline form C of compound N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine, the method comprising the following steps: a) Suspend variant A in a solvent mixture containing at least 50% dichloromethane; b) Allow the suspension to equilibrate at room temperature for approximately 4 weeks; c) Separate C-type components that are in solid form (e.g., by filtration).

[0102] In one aspect of the above implementation scheme, the solvent mixture is MeOH / dichloromethane 50:50 (v / v).

[0103] In another embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide in crystalline form (type A, type B, or a combination thereof), and at least one pharmaceutically acceptable carrier, diluent, or excipient. In a specific embodiment, the present invention relates to a pharmaceutical composition comprising crystalline form A, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In yet another aspect, the present invention relates to a pharmaceutical composition comprising crystalline form A in a substantially pure form. In yet another aspect, the present invention relates to a pharmaceutical composition comprising crystalline form B in a substantially pure form. In yet another embodiment, the invention relates to a pharmaceutical formulation comprising crystalline form A and further comprising at least one other solid form of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. In one aspect of this embodiment, the other solid form is crystalline form B. In yet another embodiment, the other solid form is an amorphous form of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

[0104] In other embodiments, the invention relates to a combination, specifically a pharmaceutical combination, comprising a therapeutically effective amount of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide in crystalline form (type A, type B, or a combination thereof), and one or more therapeutic agents.

[0105] In a specific embodiment, the present invention relates to a pharmaceutical combination comprising crystalline form A and one or more therapeutic agents. In yet another aspect, the present invention relates to a pharmaceutical combination comprising crystalline form A in a substantially pure form and one or more therapeutic agents. In yet another aspect, the present invention relates to a pharmaceutical combination comprising crystalline form B in a substantially pure form and one or more therapeutic agents. In yet another embodiment, the present invention relates to a pharmaceutical combination comprising crystalline form A and further comprising at least one other solid form of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. In one aspect of this embodiment, the other solid form is crystalline form B. In yet another embodiment, the other solid form is the amorphous form of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide.

[0106] In another embodiment, the present invention provides a pharmaceutical combination as described herein, wherein the therapeutic agent is independently selected from the group consisting of: immunosuppressants or immunomodulators or other anti-inflammatory agents (e.g. for the treatment or prevention of acute or chronic rejection or inflammation and autoimmune diseases of allogeneic grafts or xenografts) or chemotherapeutic agents (e.g., antiproliferative agents of malignant cells). For example, the crystalline form of a compound having formula (I) can be used in combination with: calcineurin inhibitors, such as cyclosporine A or FK 506; mTOR inhibitors, such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA-93, biolimus-7, or basiloxane-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; imidazolidinedin; mycophenolic acid or its salt; mycophenolate mofetil; 15-deoxyguanidin or its immunosuppressive homologues, analogues, or derivatives; PKC inhibitors, such as those disclosed in WO Compounds from WO 02 / 38561 or WO 03 / 82859, such as those in Examples 56 or 70; JAK3 kinase inhibitors, such as N-benzyl-3,4-dihydroxy-benzylidene-cyanethoxylamine α-cyano-(3,4-dihydroxy)-]N-benzylcinnamylamine (tyrosine phosphorylation inhibitor AG 490), styracin 25-C (PNU156804), [4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P131), [4-(3'-bromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P154), [4-(3',5'-dibromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] WHI-P97, KRX-211, 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-sideoxy-propionitrile, in free form or in pharmaceutically acceptable salt form, such as monocitrate (also known as CP-690,550), or compounds disclosed in WO 04 / 052359 or WO 05 / 066156; sphingosine-1-phosphate receptor modulators such as FTY720 (fingolimod), or those disclosed in WO Compounds in 2005 / 000833; immunosuppressive monoclonal antibodies, such as monoclonal antibodies against leukocyte receptors, such as MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or ligands thereof;Other immunomodulatory compounds, such as recombinant binding molecules having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, such as at least the extracellular portion of CTLA4 that binds to a non-CTLA4 protein sequence, such as CTLA4Ig (e.g., designated ATCC 68629) or a mutant thereof, or a mutant thereof, such as LEA29Y; adhesion molecule inhibitors, such as LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists, or VLA-4 antagonists; or chemotherapeutic agents, such as paclitaxel, gemcitabine, cisplatinum, doxorubicin, or 5-fluorouracil; or anti-infective agents. Further co-occurring conjugates of compounds having formula (I) may be selected from: PI3K inhibitors (e.g., pan- or α, β, γ, δ-selective), TNF inhibitors, IL1β inhibitors, IL17 inhibitors, and inhibitors of IL6 or IL receptors.

[0107] In one embodiment, the present invention relates to a method of treating a disease or disorder typically improved by BTK inhibition in a subject in need, the method comprising: administering, alone or in combination with one or more therapeutic agents, a therapeutically effective amount of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide in a crystalline form (type A, type B, or a combination thereof, preferably type A).

[0108] In another embodiment, the invention relates to a method of treating diseases or disorders (e.g., inflammatory and autoimmune diseases, and lung and respiratory tract inflammation) that are typically improved by inhibiting BTK in a subject in need, the method comprising administering, alone or in combination with one or more therapeutic agents, the pharmaceutical composition described herein to the subject.

[0109] In another embodiment, the present invention relates to a method of treating diseases or disorders (such as inflammatory and autoimmune diseases and lung and respiratory tract inflammation) that are typically improved by inhibiting BTK in a subject in need, the method comprising administering to the subject a combination of drugs as described herein.

[0110] In one embodiment, the present invention relates to the use of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide in crystalline form (type A, type B, or a combination thereof, or preferably type A), alone or in combination with one or more therapeutic agents, for the treatment of diseases or disorders typically improved by BTK inhibition (e.g., inflammatory and autoimmune diseases, as well as lung and respiratory tract inflammation).

[0111] In yet another embodiment, the present invention relates to the crystalline form (type A, type B, or a combination thereof, or preferably type A) of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide for use in the treatment of diseases or disorders typically improved by BTK inhibition, such as inflammatory and autoimmune diseases and inflammation of the lungs and respiratory tract.

[0112] In yet another embodiment, the invention relates to the crystalline form (type A, type B, or a combination thereof, or preferably type A) of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide and a combination of one or more therapeutic agents for use in the treatment of diseases or disorders typically improved by inhibiting BTK.

[0113] In one embodiment, the invention relates to methods of treatment, uses, compounds for use, or combinations for use as described herein, wherein diseases or disorders typically improved by inhibiting BTK are selected from inflammatory and autoimmune diseases as well as lung and respiratory tract inflammation. More specifically, diseases or disorders typically improved by BTK inhibition are selected from autoimmune diseases, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and transplant rejection; diseases in which antibody production, antigen presentation, cellular mediator production, or lymphoid organogenesis are abnormal or undesirable; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombocytopenic purpura, chronic urticaria (chronic spontaneous urticaria, induced urticaria), chronic allergy (atopic dermatitis, etc.). Contact dermatitis, allergic rhinitis, atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Gubaside syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism; cancers of hematopoietic origin, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenstrom disease. Preferably, diseases or disorders that are typically improved by inhibiting BTK are selected from rheumatoid arthritis; chronic urticaria, preferably chronic spontaneous urticaria; Sjögren's syndrome, multiple sclerosis, or asthma. []

[0114] The crystalline shape A described in this paper has been found to have advantageous properties.

[0115] The A-form of the compound having formula (I) is the most stable form. The A-form is physically stable when exposed to high levels of % RH and under prolonged stress conditions. The A-form is also stable in suspension in non-chlorinated solvents (e.g., solvents other than dichloromethane and chloroform).

[0116] If it is type A of the present invention, due to its non-hygroscopic nature, it retains its physicochemical properties regardless of the relative humidity of the surrounding atmosphere. This facilitates a simpler and more reliable manufacturing process and easier storage of pharmaceutical products containing type A. Furthermore, crystalline form A retains its crystal structure even when subjected to harsh temperature and / or humidity stress conditions, or when subjected to prolonged pulping in various solvents.

[0117] It was found that chloroform and dichloromethane solvents led to the formation of variant B and / or variant C.

[0118] Variant C is a metastable form because it transforms into variant B at room temperature or by heating at 50°C.

[0119] Variant B is stable at temperatures up to 170°C, but it transforms into variant A above 170°C. [Drug composition, dosage, and administration] []

[0120] In one embodiment, the crystalline forms of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide described herein can be used alone or can be formulated into a pharmaceutical composition that further contains at least one pharmaceutically acceptable excipient, and typically contains at least two or more pharmaceutically acceptable excipients. Some suitable excipients are disclosed herein. Other excipients known in the art may be used without departing from the purpose and scope of this application.

[0121] In some embodiments, the present invention utilizes a pharmaceutical composition comprising the compounds of the present invention and pharmaceutically acceptable excipients.

[0122] As used herein, the term "pharmaceuticalally acceptable excipient" includes any and all solvents, carriers, diluents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal, antioxidant), isotonic agents, absorption delay agents, salts, drug stabilizers, binders, additives, swelling agents, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like and combinations thereof, as will be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). It should be understood that this application considers the use of any conventional excipient in any therapeutic or pharmaceutical composition unless the conventional excipient is incompatible with the active ingredient.

[0123] The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical composition of this invention can be in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). The pharmaceutical composition can undergo routine pharmaceutical processes (such as sterilization) and / or may contain conventional inert diluents, lubricants, carriers or buffers, and excipients (such as solvents, preservatives, stabilizers, wetting agents, emulsifiers, and swelling agents).

[0124] Typically, these pharmaceutical formulations comprise tablets or capsules containing an active ingredient along with at least one excipient, such as: a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; in the case of tablets, also comprising... c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; if desired; d) Carriers, such as aqueous media containing co-solventizing materials, such as captisol, PEG, glycerol, cyclodextrin, etc.; e) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and / or f) Adsorbents, colorants, flavoring agents, and sweeteners.

[0125] Tablets can be film-coated or enteric-coated using methods known in the art.

[0126] Preferably, the compound or composition is prepared for oral administration, such as tablets or capsules, and, as needed, packaged in multiple-dose forms suitable for storage and / or dispensing unit doses of the pharmaceutical product. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0127] Tablets may contain an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0128] The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can promote the degradation of certain compounds.

[0129] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-aqueous components and under low moisture or low humidity conditions. The anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, it is preferable to use materials known to prevent exposure to water to package the anhydrous compositions so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastic, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0130] The present invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate of decomposition of the compounds of the present invention as active ingredients. Such agents (referred to herein as "stabilizers") include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers.

[0131] For subjects weighing approximately 50-70 kg, the pharmaceutical composition or combination of the present invention may be in the form of one or more active ingredients at a unit dose of approximately 1-1000 mg, or approximately 1-500 mg, or approximately 1-250 mg, or approximately 1-150 mg, or approximately 0.5-100 mg, or approximately 10-50 mg of active ingredient. Preferably, the pharmaceutical composition or combination of the present invention may be in the form of a unit dose of approximately 10 mg, approximately 25 mg, or approximately 50 mg. The therapeutically effective dose or amount of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition, disorder, or disease being treated, or its severity. A physician, clinician, or veterinarian with ordinary skills can readily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of the disorder or disease.

[0132] The above-described dosage characteristics are demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and products. The compounds of the present invention can be applied in vitro in solution form (e.g., preferably an aqueous solution), and in vivo, either enterically, parenterally, or preferably intravenously, as a suspension or in an aqueous solution. In vitro doses can range from about 10⁻³ mol to about 10⁻⁹ mol. Depending on the route of administration, the effective therapeutic dose in vivo can range from about 0.1 to 500 mg / kg, or from about 1 to 100 mg / kg. Preferably, the effective therapeutic dose in vivo is from about 10 mg to about 200 mg daily, for example, from about 10 mg, about 20 mg, about 25 mg, about 35 mg, about 50 mg, about 100 mg, or about 200 mg daily. Preferably, the effective therapeutic dose in vivo is selected from about 10 mg, about 35 mg, about 50 mg, or about 100 mg once daily. Preferably, the effective therapeutic dose in vivo is selected from about 10 mg, about 25 mg, about 50 mg or about 100 mg, twice daily.

[0133] In other embodiments, a pharmaceutical composition is provided comprising at least one crystalline form (e.g., type A, type B, or a mixture thereof, preferably type A) according to the embodiments described above herein, and at least one pharmaceutically acceptable carrier.

[0134] Therefore, in the embodiments disclosed herein, the crystalline form (type A or type B, preferably type A) of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is provided in substantially pure form. This substantially pure crystalline form (type A or type B) of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide can be used to prepare pharmaceutical compositions that may further comprise one or more pharmaceutically acceptable excipients. [combination:] []

[0135] The crystalline form of the compound of formula (I) of the present invention (e.g., type A or type B or a mixture thereof, preferably type A) can be administered simultaneously with one or more therapeutic agents, or administered before or after the therapeutic agent. The crystalline form of the present invention can be administered separately by means of the same or different routes of administration as other pharmaceutical agents, or administered together in the same pharmaceutical composition.

[0136] The crystalline form of a compound having formula (I) can be administered as a single active ingredient or in combination with other drugs (e.g., immunosuppressants or immunomodulators) or other anti-inflammatory agents (e.g., for the treatment or prevention of acute or chronic rejection or inflammation and autoimmune diseases of allogeneic or xenografts) or chemotherapeutic agents (e.g., antiproliferative agents of malignant cells) as adjuvants. For example, compounds having formula (I) can be used in combination with: calcineurin inhibitors, such as cyclosporine A or FK 506; mTOR inhibitors, such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA-93, biolimus-7, or basiloxane-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; imidazolidinedione; mycophenolic acid or its salt; mycophenolate mofetil; 15-deoxyguanidin or its immunosuppressive homologues, analogues, or derivatives; PKC inhibitors, such as those disclosed in WO 02 / 38561 or WO In 03 / 82859, for example, compounds of examples 56 or 70; JAK3 kinase inhibitors, such as N-benzyl-3,4-dihydroxy-benzylidene-cyanethoxylamine α-cyano-(3,4-dihydroxy)-]N-benzylcinnamylamine (tyrosine phosphorylation inhibitor AG 490), styracin 25-C (PNU156804), [4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P131), [4-(3'-bromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P154), [4-(3',5'-dibromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] WHI-P97, KRX-211, 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-sideoxy-propionitrile, in free form or in pharmaceutically acceptable salt form, such as monocitrate (also known as CP-690,550), or compounds disclosed in WO 04 / 052359 or WO 05 / 066156; sphingosine-1-phosphate receptor modulators such as FTY720 (fingolimod), or those disclosed in WO Compounds in 2005 / 000833; immunosuppressive monoclonal antibodies, such as monoclonal antibodies against leukocyte receptors, such as MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or ligands thereof;Other immunomodulatory compounds, such as recombinant binding molecules having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, such as at least the extracellular portion of CTLA4 that binds to a non-CTLA4 protein sequence, such as CTLA4Ig (e.g., designated ATCC 68629) or a mutant thereof, or a mutant thereof, such as LEA29Y; adhesion molecule inhibitors, such as LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists, or VLA-4 antagonists; or chemotherapeutic agents, such as paclitaxel, gemcitabine, cisplatin, doxorubicin, or 5-fluorouracil; or anti-infective agents. Further co-occurring conjugates of compounds having formula (I) may be selected from: PI3K inhibitors (e.g., pan- or α, β, γ, δ-selective), TNF inhibitors, IL1β inhibitors, IL17 inhibitors, and inhibitors of IL6 or IL receptors. [Healing Set] []

[0137] In one embodiment, the invention provides a kit comprising two or more individual pharmaceutical compositions, at least one of which contains a crystalline form (type A, type B, or a mixture thereof, preferably type A) of a compound having formula (I). In one embodiment, the kit includes means for separately retaining the compositions, such as containers, separate bottles, or separate foil packs. An example of such a kit is blister packaging, typically used for packaging tablets, capsules, etc.

[0138] The kits of this invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer separate components at different dose intervals, or to titrate separate components relative to each other. To aid compliance, the kits of this invention typically include instructions for use.

[0139] In the combination therapy of the present invention, the crystalline form of the compound having formula (I) (i.e., type A, type B, or a mixture thereof, preferably type A) and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Moreover, the crystalline form of the compound having formula (I) and other therapeutic agents may be (i) before the combination product is dispensed to a physician (e.g., when the kit contains the crystalline form of the compound having formula (I) and other therapeutic agents); (ii) by the physician himself (or under the physician's guidance) before administration; and (iii) by the patient himself, for example, during the sequential administration of the crystalline form of the compound having formula (I) and other therapeutic agents into the combination therapy.

[0140] Therefore, the present invention provides the use of a crystalline form as described herein (i.e., type A, type B, or a mixture thereof, preferably type A) for treating diseases (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases) that are improved by inhibiting BTK, wherein the preparation of the medicament is for administration together with another therapeutic agent. The present invention also provides the use of a therapeutic agent for treating diseases (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases) that are improved by inhibiting BTK, wherein the medicament is administered together with a compound having the crystalline form of formula (I).

[0141] The present invention also provides crystalline forms of compounds having formula (I) (i.e., type A, type B, or mixtures thereof, preferably type A) for use in a method of treating a disease improved by BTK inhibition, wherein the crystalline form of the compound having formula (I) is prepared for administration together with another therapeutic agent. The present invention also provides another immunotherapeutic agent for use in a method of treating a disease improved by BTK inhibition, wherein other therapeutic agents are prepared for administration together with the crystalline form of the compound having formula (I). The present invention also provides crystalline forms of compounds having formula (I) for use in a method of treating a disease improved by BTK inhibition, wherein the crystalline form of the compound having formula (I) is administered together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease improved by BTK inhibition, wherein it is administered together with other therapeutic agents in the crystalline form of the compound having formula (I).

[0142] The present invention also provides the use of a compound having the crystalline form of formula (I) for treating diseases (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases) that are improved by inhibiting BTK, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating diseases (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases) that are improved by inhibiting BTK, wherein such patients have previously (e.g., within 24 hours) been treated with a compound having the crystalline form of formula (I). N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide [Preparation of crystal shape:] []

[0143] Crystalline shapes can be prepared by a variety of methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid-state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallizing or recrystallizing crystalline shapes from a solvent or solvent mixture include, for example, evaporating the solvent, lowering the temperature of the solvent or solvent mixture, seeding the crystal with a supersaturated solvent mixture of molecules and / or salts, freeze-drying the solvent mixture, and adding an antisolvent (extraction solvent) to the solvent mixture. Exemplary methods for preparing the crystalline shapes described herein are detailed below.

[0144] The crystals (including polymorphs) of drugs, their preparation methods, and the characterization of drug crystals are disclosed in Solid-State Chemistry of Drugs, SR Byrn, RR Pfeiffer, and JG Stowell, 2nd ed., SSCI, West Lafayette, Indiana (1999).

[0145] For crystallization techniques using solvents, the choice of one or more solvents typically depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used; for example, the compound can be dissolved in a first solvent to provide a solution, and then an antisolvent can be added to reduce the solubility of the compound in the solution and to facilitate crystal formation. The antisolvent is a solvent in which the compound has low solubility.

[0146] In one method of preparing crystals, the compound is suspended and / or stirred in a suitable solvent to provide a slurry, which may be heated to promote dissolution. As used herein, the term "slurry" refers to a saturated solution of the compound, which may also contain additional amounts of the compound to provide a non-homogeneous mixture of the compound and solvent at a given temperature. This may also be referred to as a suspension.

[0147] Seeds can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a specific polymorph or to control the particle size distribution of the crystalline product. Therefore, the required amount of seed depends on the size of the available seed and the desired size of the average product particles, as described, for example, in "Programmed Cooling of Batch Crystallizers," JW Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Typically, small-sized seeds are required to effectively control crystal growth in a batch. Small-sized seeds can be generated by sieving, grinding, or micronizing large crystals, or by microcrystallizing the solution. It should be noted that grinding or micronizing crystals does not result in any change in the crystallinity of the crystals forming the desired polymorph (i.e., becoming amorphous or another polymorph).

[0148] The cooled crystallization mixture can be filtered under vacuum, and the separated solids can be washed with a suitable solvent (such as a cold recrystallization solvent) and dried under nitrogen purging to provide the desired crystal shape. The separated solids can be analyzed by suitable spectroscopic or analytical techniques, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, etc., to ensure the optimal crystal shape of the resulting product. The resulting crystal shape is typically produced in an amount greater than about 70% by weight of the compound initially used in the crystallization process, preferably greater than 90% by weight. If necessary, the product can be co-ground or passed through a screen to deplete the product.

[0149] Alternatively, the crystalline shape can be prepared directly from the reaction medium of the final method used to prepare N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. This can be achieved, for example, by using a solvent or mixture of solvents in the final method step from which N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide can be crystallized. Furthermore, the crystalline shape can be obtained by distillation or solvent addition techniques.

[0150] In addition to the methods briefly discussed below, it should be understood that a variety of analytical methods can be used to characterize any material described herein.

[0151] The following non-limiting examples illustrate this disclosure. [] [Example] [] [Example] [1] [Anhydrous crystal shape] [A] [Preparation]

[0152] N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzylamine (Int-10, as disclosed in WO 2015 / 079417) and sodium carbonate were suspended in ethyl acetate and heated to 50°C. A solution of acrylic anhydride in ethyl acetate (20% w / w) was added to the suspension. The reaction mixture was stirred at 50°C for about 30 min. After adding water, the reaction mixture was stirred at 65°C for about 30 min.

[0153] Subsequently, the phases were separated and the aqueous phase was removed at 60°C. The organic phase was washed with 0.05 M sulfuric acid and the aqueous phase was removed at 60°C. Afterward, the organic phase was washed with water and the aqueous phase was removed at 60°C. The final organic phase was treated by low-in-particle filtration. Distillation was carried out under reduced pressure at an internal temperature of 60°C to remove some of the solvent mixture, while ethyl acetate was added to maintain an approximately constant solvent level. This reduced the water content. (If necessary, a type A seed suspension in ethyl acetate was added to the solution). The suspension was stirred for at least 15 min. Further distillation was then carried out under reduced pressure at an internal temperature of 60°C to remove some of the solvent mixture, while ethyl acetate was added to maintain an approximately constant solvent level.

[0154] The suspension was stirred at 60°C for 30 min, cooled to 30°C over 200 min, and stirred at 30°C for 30 min. Final distillation was performed under reduced pressure at an internal temperature of 30°C, with ethyl acetate added to maintain a roughly constant solvent level. After stirring at 30°C for 120 min, the suspension was cooled to 0°C over 300 min and stirred at 0°C for at least 240 min. The product was separated by centrifugation, and the filter cake was washed twice with ethyl acetate. The separated wet product was dried under vacuum on a tray in a drying oven at 40°C. Crystalline form A was obtained. Variant A was characterized by HR-XRPD, LCMS, TGA, and DSC. [Example] [2] [Anhydrous crystal shape] [C] [Preparation]

[0155] Variant A (Example 1) was suspended in dichloromethane at 50°C for 3 days. The suspension was then filtered through a Buchner filter. The solids were recovered by filtration and dried overnight under vacuum (200 mbar) at room temperature to obtain variant C. Variant C was stored at -20°C to prevent further conversion. [Example] [3] [Anhydrous crystal shape] [B] [Preparation]

[0156] Variant C (Example 2) was placed at room temperature and its conversion to variant B was monitored by HR-XRPD, and the conversion was completed after 5 days.

[0157] Variant B and variant C were characterized using HR-XRPD, LCMS, TGA, and DSC. [Example] [4] High-resolution powder [X-] [Ray diffraction] []

[0158] The solid was finely ground in a mortar with a pestle. An 8 mm borosilicate glass capillary (0.3 mm in diameter) was filled with the compound and carefully placed in a diffractometer.

[0159] HR-XRPD maps were collected at 296 K on a Bruker D8 Advance system equipped with a LynxEye solid-state detector. The radiometric system used for data collection was monochromated by a germanium crystal using Cu Kα1 (λ = 1.54056 Å). Diffraction data for variant A were collected in the range of 4–50° 2θ, and diffraction data for variants B and C were collected in the range of 3–41.5° 2θ.

[0160] [ [surface] [1] [Anhydrous crystal shape] [A] [of] [X-] [X-ray powder diffraction data] [] [2θ [°]] [d] [value] [[Å]] [strength] [[%]] 7.80 11.33 44 9.28 9.52 18 10.17 8.69 12 12.03 7.35 twenty two 13.66 6.48 51 15.68 5.65 62 16.02 5.53 18 17.81 4.98 twenty two 18.30 4.84 66 18.73 4.73 twenty one 19.28 4.60 27 19.90 4.46 26 20.25 4.38 9 20.76 4.28 11 21.13 4.20 10 22.10 4.02 15 23.47 3.79 57 23.96 3.71 100 24.25 3.67 12 24.86 3.58 14 25.22 3.53 20 25.58 3.48 14 27.23 3.27 16 29.60 3.02 26

[0161] [ [surface] [2] [Anhydrous crystalline form] [B] [of] [X-] [X-ray powder diffraction data] [] [2θ [°]] [d] [value] [[Å]] [strength] [[%]] 5.90 14.96 29 6.78 13.03 59 7.86 11.24 35 8.35 10.58 25 11.11 7.96 62 12.10 7.31 49 12.69 6.97 37 13.07 6.77 28 13.63 6.49 19 13.93 6.35 twenty two 14.53 6.09 19 14.86 5.96 29 15.34 5.77 16 15.83 5.59 40 16.11 5.50 19 16.42 5.39 24 16.81 5.27 21 17.05 5.20 18 17.96 4.94 57 19.05 4.66 27 19.38 4.58 21 20.22 4.39 58 20.65 4.30 39 20.99 4.23 100 21.66 4.10 24 22.32 3.98 24 22.66 3.92 30 23.38 3.80 27 24.07 3.69 75 24.92 3.57 22 25.35 3.51 43 25.71 3.46 31

[0162] [ [surface] [3] [Anhydrous crystal shape] [C] [of] [X-] [X-ray powder diffraction data] [] [2θ [°]] [d] [value] [[Å]] [strength] [[%]] 5.91 14.95 100 11.92 7.42 84 12.07 7.33 40 12.54 7.05 49 12.97 6.82 25 13.92 6.36 20 14.46 6.12 28 14.68 6.03 twenty two 15.32 5.78 59 17.05 5.20 68 18.00 4.93 33 18.21 4.87 20 19.03 4.66 57 19.20 4.62 23 19.92 4.45 27 20.23 4.39 26 20.87 4.25 22 21.03 4.22 34 21.19 4.19 31 21.62 4.11 19 22.84 3.89 20 23.40 3.80 33 23.71 3.75 42 24.34 3.65 17 25.09 3.55 16 25.31 3.52 26 26.15 3.40 29 26.47 3.37 20 26.91 3.31 23 27.17 3.28 28 [Example] [5] Differential scanning calorimetry (DSC) [DSC] [)] []

[0163] Melting characteristics were obtained from DSC thermal analysis plots and recorded using a heat flux DSC822e instrument (Mettler-Toledo GmbH, Switzerland). The temperature and enthalpy of the DSC822e were calibrated using a small piece of indium (melting point 156.6°C; ΔH = 28.45 J / g). Samples were sealed in standard 40 μl aluminum disks, either with pinholes or hermetically sealed, and heated in the DSC from -20°C to 300°C at heating rates of 2°C / min, 5°C / min, 10°C / min, or 20°C / min. During measurements, the DSC instrument was purged with dry N2 gas at a flow rate of 50 ml / min.

[0164] Cyclic DSC was performed using the same equipment. The sample was sealed in a standard 40 μl aluminum disk, punctured with a needle, and heated in DSC from 20°C to 195°C, cooled from 195°C to -20°C, and then heated again from -20°C to 300°C. The heating and cooling rates were 10°C / min.

[0165] The accuracy of sample temperature measured using this method is within approximately ±1°C, and the heat of fusion can be measured within approximately ±5% relative error.

[0166] DSC measurements were performed on variants A, B, and C at different heating rates in open and closed pans, between -20°C and 300°C.

[0167] Figures 2, 5, and 8 report the DSC traces of variants A, B, and C recorded in the open pan, respectively. The onset temperatures of the exothermic / endothermic events observed in the DSC traces are reported in Tables 4, 5, and 6, respectively.

[0168] In both sets of DSC measurements, an overall shift of thermal events to higher temperatures was observed by increasing the heating rate and expanding the event.

[0169] The DSC curves for variant A show that the initial melting temperatures for both the open and closed discs are in the range of 193-195°C. In the DSC measurements for variant B, the endothermic / exothermic events between 170°C and 180°C may be related to the melting and recrystallization of variant B into A.

[0170] The presence of endothermic / thermal events between 170°C and 180°C in the DSC trace of variant C confirms that variant C is transformed into variant B by heating.

[0171] [ [surface] [4]: The onset temperature and enthalpy of the endothermic event determined in DSC measurements of variant A in an open pan at heating rates of 2, 5, 10 and 20 °C / min. heating rate (°C / min) Endothermic events Starting temperature (°C) ΔH (J / g) 2 193.2 95 5 194.0 120 10 194.2 118 20 195.4 106

[0172] [ [surface] [5]: The onset temperatures and enthalpies of endothermic and exothermic events determined in DSC measurements of variant B in an open pan at heating rates of 2, 5, 10 and 20 °C / min. heating rate (°C / min) Endothermic event 1 Starting temperature (°C) ΔH (J / g) Heat release event 2 Starting temperature (°C) ΔH (J / g) Endothermic event 3 Starting temperature (°C) ΔH (J / g) 2 169.6 13 172.3 12 194.0 112 5 169.9 17 173.5 15 194.5 119 10 170.5 twenty four 175.1 twenty two 194.8 112 20 171.0 26 178.8 twenty two 195.3 112

[0173] [ [surface] [6]: The onset temperatures and enthalpies of endothermic and exothermic events determined by DSC measurements of variant C in an open pan at heating rates of 2, 5, 10, and 20 °C / min. heating rate (°C / min) Exothermic event 1 Starting temperature (°C) ΔH (J / g) Endothermic event 1 Starting temperature (°C) ΔH (J / g) Endothermic event 2 Starting temperature (°C) ΔH (J / g) Endothermic event 3 Starting temperature (°C) ΔH (J / g) 2 - - 170.4 28 172.3 twenty three 193.5 112 5 - - 170.9 28 173.6 27 194.6 110 10 - - 171.3 31 175.5 26 195.5 102 20 98.6 4 171.8 43 177.5 31 195.4 99 [Example] [6] Thermogravimetric Analysis (TGA) [TGA] [):] []

[0174] Mass loss due to solvent or water loss in the crystal was determined using TGA / SDTA (single differential calorimetry) and TGMS (thermogravimetric analysis coupled with mass spectrometry). Sample weight was monitored during heating in a TGA / DSC 3+ STARe system (Mettler-Toledo AG, Switzerland), and weight versus temperature profiles were obtained. Temperature calibration of the TGA / DSC 3+ was performed using indium and aluminum samples. The sample (approximately 2 mg) was weighed into a 100 μL aluminum crucible and sealed. A puncture was made in the seal, and the crucible was heated in the TGA from 25°C to 300°C at a heating rate of 10°C / min. The mixture was purged with dry N2 gas. Gas from the TGA sample was analyzed using an Omnistar GSD 301 T2 mass spectrometer (Pfeiffer Vacuum GmbH, Germany). The latter is a quadrupole mass spectrometer capable of analyzing mass in the temperature range of 0–200 amu. Report temperature in degrees Celsius (°C) and report weight loss as a percentage.

[0175] TGA / SDTA analysis of variant A (Figure 3) showed a mass loss of 0.3% in the temperature range of 40°C–200°C, indicating that variant A is anhydrous. The endothermic peak around 190°C in the SDTA curve can be attributed to the melting of the compound. Thermal degradation occurred above 240°C. []

[0176] [picture] [3.] TGA / SDTA analysis of variant A (heating rate 10°C / min). A mass loss of 0.3% was recorded in the range of 40°C–200°C. Thermal decomposition occurred above 240°C.

[0177] TGA / STDA analysis of variant B (Figure 6) showed a mass loss of 0.2% in the temperature range of 40°C–160°C. Therefore, variant B is anhydrous. The events occurring above 160°C in the SDTA curve are attributed to the melting and recrystallization of variant B into variant A, followed by the final melting of variant A. Thermal degradation occurred above 240°C.

[0178] [picture] [6.] TGA / SDTA analysis of variant B (heating rate 10°C / min). A 0.2% mass loss was recorded in the range of 40°C–160°C. Thermal decomposition occurred above 240°C.

[0179] TGMS analysis of variant C (Figure 9) showed a mass loss of 0.01% in the temperature range of 40°C–150°C, indicating that variant C is an anhydrous crystalline phase. Thermal degradation occurred above 240°C. []

[0180] [picture] [9.] TGA / SDTA (20A) and TGMS (20B) analysis of variant C (heating rate 10°C / min). 0.01% mass loss was recorded in the range of 40°C–150°C. Thermal decomposition occurred above 240°C. [Example] [4] [Comparison of physicochemical stability] []

[0181] Variations A, B, and C are subjected to the following stress conditions: • 80°C in sealed vials for 1 month; • 80°C / 75% RH in open vials for 1 month; • 100°C in sealed vials for 3 days;

[0182] Subsequently, the solids were analyzed by HR-XRPD, TGMS and HPLC to assess potential solid phase transitions, drying weight loss and chemical purity.

[0183] After stability testing, all solids were analyzed by HR-XRPD, TGMS, and HPLC. The results of the physicochemical stability tests are reported in Table 7. [HPLC] [condition] Automatic sampler temperature: 15°C Column: Waters Sunfire C18 (100 x 4.6 mm; 3.5 μm). Column temperature: 35°C Flow cell: 10 mm path Gradient: Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Flow rate: 1.0 ml / min Gradient: Time [min]: Solution A: Solution B: 0 90% 10% 9 10% 90% 10 90% 10% 11 90% 10% Execution time: 11 min

[0184] [ [surface] [7] Results of physicochemical stability tests on variants A, B and C. Initial variant Stress conditions HR-XRPD recovers solids Loss on drying (%) HPLC determination of recovery (%) A 80°C, 1 month, sealed vial A 0.003 98.0 B 80°C, 1 month, sealed vial B 0.009 99.8 C 80°C, 1 month, sealed vial B 0.007 101.8 A 80°C / 75% RH 1 month, open bottle A 0.003 104.5 B 80°C / 75% RH 1 month, open bottle B 0.004 102.5 C 80°C / 75% RH 1 month, open bottle B 0.006 100.3 A 100°C, 3 days, sealed vials A 0.003 98.4 B 100°C, 3 days, sealed vials B 0.004 103.0 C 100°C, 3 days, sealed vials B 0.003 99.7

[0185] After 1 month of exposure to 80°C and 3 days of exposure to 100°C, variant C transformed into variant B. The XRPD plots of variants A and B remained unchanged. Conversely, under all three test conditions, variant C transformed into variant B.

[0186] TGMS analysis showed no obvious moisture absorption, therefore the solid system is not hygroscopic.

[0187] The chemical purity of the sample was not affected by exposure to high temperatures and high RH levels for 3 days or 1 month, as indicated by a recovery value close to 100%. [Example] [5] [Water Absorption Study] [] Water absorption of variant A

[0188] The water adsorption of variant A was assessed by exposing the solid material at 25°C to 80% and 92% RH for 24 hours. Subsequently, the solid was analyzed by HT-XRPD to assess any changes in the crystalline phase, and water absorption was determined by TGMS.

[0189] After 24 hours of exposure to 80% and 92% RH, variant A was physically stable. TGMS analysis showed a mass loss of 0.2% for both samples. Therefore, variant A can be considered non-hygroscopic. Water adsorption isotherms of variant A at 25°C and 40°C

[0190] Dynamic vapor adsorption (DVS): Moisture adsorption isotherms were collected on a DVS-1 system from Surface Measurement Systems (London, UK). Typical sample sizes ranged from 5 to 10 mg of solid material. The relative humidity profile was 40%→0→95%→0→95%→40%, increasing the RH level by 10% per step. Weight equilibrium time was set to a minimum of 60 minutes and a maximum of 6 hours per relative humidity step, with dm / dt of 0.002% / min.

[0191] Dynamic vapor adsorption (DVS) measurements were performed on variant A at 25°C and 40°C, with the RH curve showing 40%→0→95%→0→95%→40%, increasing by 10% RH at each step.

[0192] Variant A showed no significant water vapor absorption at either 25°C or 40°C. At 95% RH, the highest mass changes were 0.4% and 0.3% at 25°C and 40°C, respectively. The adsorption and desorption cycles were reversible, and no indication of hydrate formation was obtained by DVS measurement. The solid recovered after DVS measurement was still variant A. DVS measurements of variants B and C

[0193] DVS measurements performed on variants B and C yielded similar results to those collected for variant A. Neither phase showed significant water vapor absorption. At 95% RH, the maximum recorded mass increase for both phases was 0.3%.

[0194] After DVS measurement, the XRPD plot of variant B remained unchanged. In contrast, the solid mixture of variants B and C was recovered after DVS measurement of variant C, which is likely due to the spontaneous conversion of variant C to B at 25°C. [Example] [5] Stability in solvents [] Stability of variant A in solvent

[0195] Suspensions of variant A were prepared in 23 selected solvents and equilibrated at room temperature (RT) for 4 weeks and at 50°C for 2 weeks. After equilibration, the solids were separated from the liquid phase, dried under ambient conditions and vacuum (5 mbar / 50°C), and analyzed by HT-XRPD.

[0196] When the suspension dissolved, the solvent was removed by evaporation under vacuum (initially at 200 mbar / RT, then at 5 mbar / 50°C). The liquid phase was also evaporated under the same conditions. The residual solids were analyzed by HT-XRPD.

[0197] The experimental details and results of the solvent equilibrium experiments conducted at room temperature and 50°C are shown in Tables 8 and 9, respectively.

[0198] [ [surface] [8]: Experimental conditions and results of a 4-week solvent equilibrium experiment on variant A at room temperature. The symbol (-) indicates that no solid was recovered. The symbol (ly) indicates that the amount of material recovered was low (low yield). ML is the mother liquor. Mass (mg) solvent Volume (μL) Concentration (mg / mL) solid after curve HT-XRPD Environmental vacuum evaporation Drying ML 101.3 1,4-2㗁𠮿 500 202.6 have A A - 103.2 2-Methyl-2-butanol 500 206.4 have A A - 96.1 acetone 500 192.2 have A A - 91.9 Acetonitrile 500 183.8 have A A - 102.9 aniline 500 205.8 have A A - 100.8 chloroform 500 201.6 have C B B 102.0 Cyclopentanone 500 204.0 have A A - 104.0 DCM 500 208.0 have C B+C - 103.2 DMSO 500 206.4 none - - A 105.7 ethanol 500 211.4 have A A - 107.4 Isopropyl acetate 500 214.8 have A A - 102.2 MeOH 500 204.4 have A A A(ly) 102.9 MeOH / acetone 50 / 50 500 205.8 have A A A(ly) 91.3 MeOH / Chloroform 50 / 50 500 182.6 have A A A 93.8 MeOH / DCM 50 / 50 500 187.6 have C B+C B(ly) 108.3 MeOH / 1,4-dichlorodimethylamine 50 / 50 500 216.6 have A A A 101.3 MeOH / Pyridine 50 / 50 500 202.6 have A A A 99.6 MeOH / THF 50 / 50 500 199.2 have A A A 105.2 Nitromethane 500 210.4 have A A - 174.0 1-Methyl-2-pyrrolidone 500 348.0 have A A A 93.4 Pyridine 500 186.8 have A A A 91.3 THF 500 182.6 have A A A 101.0 water 500 202.0 have A A -

[0199] [ [surface] [9] [.] Experimental conditions and results of a 2-week solvent equilibrium experiment on variant A at 50°C. The symbol (-) indicates no solids were recovered. The symbol (ly) indicates a low amount of material recovered. Mass (mg) solvent Volume (μL) Concentration (mg / mL) solid after curve HT-XRPD Environmental vacuum evaporation Drying ML 103.9 1,4-2㗁𠮿 500 207.8 have A A A 91.7 2-Methyl-2-butanol 500 183.4 have A A - 94.0 acetone 500 188.0 have A A A(ly) 100.4 Acetonitrile 500 200.8 have A A A(ly) 93.2 aniline 500 186.4 have A A A(ly) 93.8 chloroform 500 187.6 have A A A+B 97.6 Cyclopentanone 500 195.2 have A A A 99.6 DCM 500 199.2 have C B B 90.4 DMSO 500 180.8 none - - A 92.5 ethanol 500 185.0 have A A A 97.9 Isopropyl acetate 500 195.8 have A A A(ly) 98.1 MeOH 500 196.2 have A A A 95.2 MeOH / acetone 50 / 50 500 190.4 have A A A 100.9 MeOH / Chloroform 50 / 50 500 201.8 none - - A 98.9 MeOH / DCM 50 / 50 500 197.8 none - - B 94.8 MeOH / 1,4-dichlorodimethylamine 50 / 50 500 189.6 have A A A 98.5 MeOH / Pyridine 50 / 50 500 197.0 have A A A 95.2 MeOH / THF 50 / 50 500 190.4 have A A A 99.1 Nitromethane 500 198.2 have A A A(ly) 191.3 1-Methyl-2-pyrrolidone 500 382.6 none - - A 97.0 Pyridine 500 194.0 have A A A 101.4 THF 500 202.8 have A A A 97.3 water 500 194.6 have A A A(ly) Stability of variants B and C in solvents

[0200] Suspensions of variants B and C were prepared in 15 selected solvents and equilibrated at room temperature for 2 weeks, followed by equilibration at 50°C for 1 week. After equilibration, the solids were separated from the liquid phase, dried under ambient conditions and vacuum (5 mbar / 50°C), and analyzed by HT-XRPD.

[0201] When the suspension dissolved, the solvent was removed by evaporation under vacuum (initially 200 mbar / RT, then 5 mbar / 50°C). The liquid phase was also evaporated under the same conditions. The residual solids were analyzed by HT-XRPD.

[0202] The experimental details and results of the solvent equilibrium experiments on variant B at room temperature and 50°C are reported in Tables 10 and 11, respectively.

[0203] The experimental details and results of the solvent equilibrium experiments on variant C at room temperature and 50°C are reported in Tables 12 and 13, respectively.

[0204] [ [surface]

[10] ] [.] Experimental conditions and results of a 2-week solvent equilibrium experiment on variant B at room temperature. The symbol (-) indicates no solid was recovered. The symbol (ly) indicates a low amount of recovered material. The symbol (lc) indicates poor recovery of crystalline material. (SB: solvated form) Mass (mg) solvent Volume (μL) Concentration (mg / mL) solid after curve HT-XRPD Environmental vacuum evaporation Drying ML 61.8 1,4-2㗁𠮿 600 103.0 have A A A 61.4 2-Methyl-2-butanol 800 76.8 have A A A 61.5 acetone 600 102.5 have A A - 57.4 Acetonitrile 700 82.0 have A A - 58.8 aniline 600 98.0 have A A A(ly) 59.3 chloroform 700 84.7 have A(ly) (lc) B 57.6 Cyclopentanone 600 96.0 have A A - 62.3 dichloromethane 1000 62.3 have C(lc) B+C B+SB(ly) 64.2 ethanol 600 107.0 have A A - 61.5 Isopropyl acetate 600 102.5 have A A - 62.1 methanol 600 103.5 have A A A 59.6 Nitromethane 700 85.1 have A A A(ly) 62.1 Pyridine 300 207.0 have A A A 61.2 Tetrahydrofuran 600 102.0 have A A A 60.0 water 1000 60.0 have A A -

[0205] [ [surface]

[11] [.] Experimental conditions and results of a 1-week solvent equilibrium experiment on variant B at 50°C. The symbol (-) indicates no solids were recovered. The symbol (ly) indicates a low amount of material recovered. Mass (mg) solvent Volume (μL) Concentration (mg / mL) solid after curve HT-XRPD Environmental vacuum evaporation Drying ML 64.7 1,4-2㗁𠮿 400 161.8 have A A A 62.9 2-Methyl-2-butanol 600 104.8 have A A - 60.7 acetone 400 151.8 have A A A 58.5 Acetonitrile 500 117.0 have A A A(ly) 59.3 aniline 400 148.3 have A A - 60.5 chloroform 400 151.3 have A A A 63.8 Cyclopentanone 400 159.5 have A A A 58.1 dichloromethane 800 72.6 have C B+C B+C 59.3 ethanol 400 148.3 have A A A(ly) 60.6 Isopropyl acetate 400 151.5 have A A A(ly) 58.8 methanol 400 147.0 have A A A 64.4 Nitromethane 500 128.8 have A A A 58.1 Pyridine 200 290.5 have A A A 60.1 Tetrahydrofuran 400 150.3 have A A A 59.3 water 1000 59.3 have A A -

[0206] [ [surface]

[12] [Experimental conditions and results of a 2-week solvent equilibrium experiment on variant C at room temperature. The symbol (-) indicates no solids were recovered. The symbol (ly) indicates a low amount of material recovered. (SC: solvated form)] Mass (mg) solvent Volume (μL) Concentration (mg / mL) solid after curve HT-XRPD Environmental vacuum evaporation Drying ML 70.1 1,4-2㗁𠮿 700 100.1 have A A A 66.6 2-Methyl-2-butanol 700 95.1 have A A - 65.3 acetone 700 93.3 have A A - 63.9 Acetonitrile 700 91.3 have A A - 65.1 aniline 700 93.0 have A A A(ly) 66.4 chloroform 700 94.9 have C+SC B C+SC 63.9 Cyclopentanone 500 127.8 have A A A(ly) 65.0 dichloromethane 500 130.0 have C B+C - 64.3 ethanol 700 91.9 have A A A(ly) 66.3 Isopropyl acetate 700 94.7 have A A A(ly) 69.6 methanol 500 139.2 have A A A(ly) 65.6 Nitromethane 700 93.7 have A A A(ly) 67.2 Pyridine 300 224 have A A A 65.6 Tetrahydrofuran 500 131.2 have A A A 65.2 water 1000 65.2 have A A A(ly)

[0207] [ [surface]

[13] [.] Experimental conditions and results of a one-week solvent equilibrium experiment on variant C at 50°C. The symbol (ly) indicates a low amount of material recovered. The symbol (-) indicates no solids were recovered. Mass (mg) solvent Volume (μL) Concentration (mg / mL) solid after curve HT-XRPD Environmental vacuum evaporation Drying ML 67.6 1,4-2㗁𠮿 500 135.2 have A A A 64.8 2-Methyl-2-butanol 500 129.6 have A A A(ly) 65.3 acetone 500 130.6 have A A A(ly) 68.7 Acetonitrile 500 137.4 have A A A(ly) 68.0 aniline 500 136.0 have A A - 64.1 chloroform 500 128.2 without - - SC 66.0 Cyclopentanone 300 220.0 have A A A 65.8 dichloromethane 300 219.3 have C B C(ly) 68.5 ethanol 500 137.0 have A A A(ly) 65.3 Isopropyl acetate 500 130.6 have A A - 64.3 methanol 300 214.3 have A A A 65.2 Nitromethane 500 130.4 have A A A(ly) 67.2 Pyridine 150 448.0 have A A A 66.7 Tetrahydrofuran 300 222.3 have A A A 66.8 water 1000 66.8 have A A - [Example] [6] Stability under granulation simulation experiments []

[0208] Granulation solvent was added dropwise to polycrystalline form A until the solid was fully wetted. The suspension was vortexed between each addition. The suspension was dried under vacuum. The remaining solid form was separated, and the crystallinity was analyzed by XRPD and / or DSC. The granulation solvents tested were water, ethanol, 2-propanol, acetone, and benzyl alcohol. No change in crystallinity was observed. [Example] [7] Stability under compression []

[0209] Using a hydraulic press (tablet diameter 13 mm), 100-300 mg of polycrystalline form A was compressed at 10 tons for 5 minutes. The samples were then analyzed by XRPD and DSC to examine for any changes in the polycrystalline form. Analysis showed no change in the material.

[0210] The most stable form of the compound having formula (I) was found to be variant A.

[0211] The variant A system is physically stable when exposed to high levels of % RH and under prolonged stress conditions. It is also stable under compression and granulation simulations. Variant A is stable in most solvents, except for chlorinated solvents such as chloroform and dichloromethane, or solvent mixtures containing more than 50% by volume of chlorinated solvents (e.g., dichloromethane and / or chloroform).

[0212] It was found that chlorinated solvents such as chloroform and dichloromethane lead to the formation of variants B and C. Both variants B and C are metastable forms, as variant C is converted to variant B at room temperature or by heating at 50°C, and variant B is converted to variant A above 170°C.

[0213] none

[0214] none

Claims

1. Use of a crystalline form of N-(3-(6-amino-5-(2-(N-methacrylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzoamide for the preparation of a pharmaceutical for treating chronic urticaria, the crystalline form being characterized by an X-ray powder diffraction pattern containing the following representative peaks represented by 2θ: 7.8 ± 0.2 °2θ, 9.2 ± 0.2 °2θ, and 12.0 ± 0.2 °2θ, when measured at a temperature of 25°C ± 5% and an X-ray wavelength λ of 1.5405 Å.

2. As requested in claim 1, wherein the crystalline form is further characterized by the following additional representative peaks: 18.3 ± 0.2 °2θ and 23.9 ± 0.2 °2θ, when measured at a temperature of 25°C ± 5% and an X-ray wavelength λ of 1.5405 Å.

3. As requested in item 1 or 2, wherein the crystalline form is further characterized by one or more peaks selected from the group consisting of: 13.6 ± 0.2 °2θ, 15.6 ± 0.2 °2θ, 16.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 22.1 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, 24.8 ± 0.2 °2θ, 25.2 ± 0.2 °2θ, 25.5 ± 0.2 °2θ, 27.2 ± 0.2 °2θ, and 29.6 ± 0.2 °2θ, when measured at a temperature of 25°C ± 5% and an X-ray wavelength λ of 1.5405 Å.

4. As requested in items 1, 2 or 3, wherein the crystalline form is characterized by an X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 1.

5. For the purposes of any of claims 1 to 4, wherein the crystalline form is characterized by a differential thermogravimetric curve measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min, the curve containing a single endothermic peak beginning at approximately 194°C.

6. As requested in claim 5, wherein the crystalline form has a differential scanning calorimetry (DSC) thermal analysis plot that is substantially the same as that shown in Figure 2.

7. The use of any one of claims 1 to 6, wherein the crystalline form has a decomposition point greater than 240°C as determined by thermogravimetric analysis and a drying loss of about 0.3% in the range of 40°C to 200°C.

8. As requested in claim 7, wherein the crystalline form has a thermogravimetric analysis (TGA) plot that is substantially the same as the plot shown in Figure 3.

9. The use of any of claims 1 to 8, wherein the crystalline form has a purity of more than 90% by weight.

10. For the purposes of any of claims 1 to 9, wherein the chronic urticaria is chronic induced urticaria.

11. The use of any of claims 1 to 10, wherein the crystalline form is placed in a pharmaceutical composition.

12. As claimed in claim 11, wherein the pharmaceutical composition is for oral administration.

13. As claimed in claim 12, wherein the pharmaceutical composition is in solid form.

14. As claimed in claim 13, wherein the solid form is a tablet or capsule.

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