Crystalline forms of BTK inhibitors

Abstract

This application relates to various anhydrous crystalline forms of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, as well as compositions, methods of making and methods of using the anhydrous crystalline forms. The crystalline forms are useful in the treatment of diseases and disorders that are typically ameliorated by inhibition of BTK. Such diseases and disorders can include inflammatory and autoimmune disorders, and inflammation of the lungs and airways.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present disclosure relates to a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. The present disclosure also relates to pharmaceutical compositions comprising the crystalline form, as well as methods of obtaining and using such crystalline forms in the treatment of diseases and disorders that are typically ameliorated by inhibition of Bruton's tyrosine kinase. Such diseases and disorders may include inflammatory and autoimmune disorders, and inflammation of the lungs and airways.

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

[0003] The solid form of a particular drug's active pharmaceutical ingredient (API) is often an important determinant of the drug's ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in vivo. Crystal forms arise when substances of the same composition crystallize in different lattice arrangements, resulting in different thermodynamic properties and stability specific to a particular crystal form. Crystal forms may also include different hydrates or solvates of the same compound. The determination of which form is preferred involves comparing multiple properties of the forms and selecting the preferred form based on many physical property variables. It is quite possible that one form may be preferred in situations where certain aspects, such as ease of preparation, stability, etc., are important. In other situations, another form may be preferred due to its higher dissolution rate and / or better bioavailability.

[0004] Therefore, this ability of a chemical to crystallize into multiple crystalline forms can have a significant impact on the shelf life, solubility, formulation properties, and processing properties of a drug. In addition, the action of a drug can be affected by the polymorphism of the drug molecule. Different polymorphs can have different uptake rates in the body, which can lead to higher or lower biological activity than desired. In extreme cases, undesired polymorphs can even be toxic. The occurrence of unknown crystalline forms during manufacturing can have a significant impact.

[0005] It is not yet possible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in therapeutic compositions, or which forms will exhibit such desired properties. However, by understanding which crystalline forms of a drug are possible in a particular case, researchers can maximize the desirable properties of the compound, such as solubility, formulation properties, processing properties, and shelf life. Understanding these factors early in the development of a new drug can mean a more active, more stable, or less expensive drug.

[0006] Thus, there is a need to provide a solid form of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide that has physicochemical properties that allow for the reliable manufacture of safe and effective pharmaceutical products comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

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

[0008] However, WO 2015 / 079417 does not provide information regarding the crystalline forms of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. Crystalline forms of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide have been discovered that are useful in the treatment of diseases that are typically ameliorated by inhibition of BTK. Such diseases and conditions may include inflammatory and autoimmune disorders, and inflammation of the lungs and airways.

[0009] overview In one aspect, the present invention provides three crystalline forms of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide in the free form (i.e., non-salt form). In certain embodiments, the free form is an anhydrous form of the compound of formula (I).

[0010] Embodiments of these crystalline forms include those designated herein as Form A, Form B, and Form C. The designations used herein to identify particular forms (e.g., "Form A," or "Form B," or "Form C") should not be considered limiting with respect to any other substances having similar or identical physical and chemical characteristics, but rather, it should be understood that these designations are merely identifiers that should be interpreted according to the characterization information also presented herein.

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

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

[0013] In one aspect, the present invention also provides a method for preparing crystalline form A of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, comprising the steps of: a) reacting N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide with acrylic anhydride in a non-chlorinated solvent, optionally in the presence of an inorganic base; and b) isolating crystalline form A as a solid (e.g., by anti-solvent crystallization, cooling crystallization, distillation procedures, or evaporation of the solvent). Also provided is a method comprising:

[0014] In one aspect, the invention also provides a method of treatment of a disorder mediated by BTK or ameliorated by inhibition of BTK, comprising administering to a patient in need of such treatment a therapeutically effective amount of crystalline Form A of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. Preferably, crystalline Form A is substantially phase pure.

[0015] In one aspect, the invention also provides a method of treatment of a disorder mediated by BTK or ameliorated by inhibition of BTK, comprising administering to a patient in need of such treatment an effective amount of substantially phase-pure crystalline Form B of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. Preferably, crystalline Form B is substantially phase-pure.

[0016] In one aspect, the present invention also provides the use of crystalline form A of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide for the preparation of a medicament for the treatment of a disorder mediated by BTK or ameliorated by inhibition of BTK. Preferably, crystalline form A is substantially phase pure.

[0017] In one aspect, the present invention also provides the use of substantially phase-pure crystalline form B of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide for the preparation of a medicament for the treatment of a disorder mediated by BTK or ameliorated by inhibition of BTK. Preferably, crystalline form B is substantially phase-pure.

[0018] In one aspect, the present invention also provides crystalline Form A of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide for use in treating a disorder mediated by BTK or ameliorated by inhibition of BTK. Preferably, crystalline Form A is substantially phase pure.

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

[0020] Thus, the crystalline forms of the compound of Formula (I) described herein are useful in the treatment of the following diseases or disorders that are mediated by BTK or are ameliorated by inhibition of BTK: autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases in which antibody production, antigen presentation, cytokine production, or lymphoid tissue formation is abnormal or undesirable; such as rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), gout, rheumatoid arthritis, and the like. Pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic idiopathic urticaria, induced urticaria), chronic allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease (morbus Crohn's disease), pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, B-cell mediated hyperacute, acute, and chronic graft rejection; thromboembolic disorders, myocardial infarction, angina, stroke, ischemic disorders, pulmonary embolism; cancers of the hematopoietic organs, 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; myelofibrosis with myeloid metaplasia; and Waldenstrom's disease.

[0021] The crystalline forms of the compound of formula (I) are particularly useful in the treatment of rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; Sjogren's syndrome, multiple sclerosis, atopic dermatitis, or asthma. [Brief description of the drawings]

[0022] [Figure 1] 1 shows an illustrative XRPD spectrum of the anhydrous crystalline form of compound of formula (I), designated herein as Form A, showing the angle 2θ (2 theta) on the X-axis and the relative intensity on the Y-axis. [Diagram 2] 1 shows an exemplary DSC of the anhydrous crystalline form of the compound of formula (I), designated herein as Form A. [Diagram 3] 1 shows an exemplary TGA of the anhydrous crystalline form of the compound of formula (I), designated herein as Form A. [Figure 4] 1 shows an illustrative XRPD spectrum of the anhydrous crystalline form of compound of formula (I), designated herein as Form B, showing the angle 2θ (2 theta) on the X-axis and the relative intensity on the Y-axis. [Diagram 5] 1 shows an exemplary DSC of the anhydrous crystalline form of the compound of formula (I), designated herein as Form B. [Figure 6] 1 shows an exemplary TGA of the anhydrous crystalline form of the compound of formula (I), designated herein as Form B. [Figure 7] 1 shows an illustrative XRPD spectrum of the anhydrous crystalline form of compound of formula (I), designated herein as Form C, showing the angle 2θ (2 theta) on the X-axis and the relative intensity on the Y-axis. [Figure 8] 1 shows an exemplary DSC of the anhydrous crystalline form of the compound of formula (I), designated herein as Form C. [Figure 9] 1 shows an exemplary TGA of the anhydrous crystalline form of the compound of formula (I), designated herein as Form C.

[0023] A more detailed list of the XRPD peaks for each of Forms A, B, and C is set forth below in Tables 1 and 2, respectively, where the % relative intensity (I / I 0x100) are also described. It should be understood that in an X-ray powder diffraction spectrum or pattern, there is inherent variation in values ​​measured in degrees 2θ (°2θ), for example, as a result of instrumental variability (including instrument-to-instrument differences). As such, it should be understood that there is variation in XRPD peak measurements of up to ±0.2°2θ, but such peak values ​​will still be considered representative of the particular solid forms of the crystalline materials described herein. It should be understood that other measurements (e.g., relative intensities and water content) from XRPD and DSC / TGA experiments may vary, for example, as a result of sample preparation and / or storage and / or environmental conditions, but such measurements will still be considered representative of the particular solid forms of the crystalline materials described herein.

[0024] Detailed Description of the Disclosure definition As used herein, the terms "about" and "substantially" indicate that these values ​​may vary with respect to features (e.g., endotherms, endothermic peaks, exotherms, baseline shifts, etc.). With respect to X-ray diffraction peak positions, "about" or "substantially" means that typical peak position and intensity variations are taken into account. For example, one skilled in the art will understand that peak positions (2θ) will exhibit some inter-instrument variation (typically on the order of 0.2°). In some cases, this variation may be higher than 0.2° depending on instrument calibration differences. Furthermore, one skilled in the art will understand that relative peak intensities exhibit inter-instrument variation as well as variation due to crystallinity, preferred orientation, sample surface prepared, and other factors known to those skilled in the art, and should be interpreted only as a qualitative measure. In the case of DSC, the observed temperature variations will depend on the rate of temperature change as well as the sample preparation technique and the particular instrument used. Thus, the endotherm / melting point values ​​reported herein with respect to DSC / TGA thermograms may vary by ±5°C (and still be considered characteristic of the particular crystalline form described herein). When used in the context of other characteristics (eg, weight percent (wt %), reaction temperature), the term "about" indicates a variance of ±5%.

[0025] The terms "crystalline form", or "crystalline modification", or "polymorphic form", or "polymorph" are used interchangeably herein. As used herein, "polymorph" refers to crystalline forms that have the same chemical composition but differ in the spatial arrangement 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.

[0026] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that is not crystalline. Amorphous solids do not exhibit distinct X-ray diffraction patterns.

[0027] As used herein, "substantially pure" when used in reference to a form means a compound having a purity of greater than 90% by weight (e.g., greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, and about 100% by weight) of the compound of formula (I) based on the weight of the compound. The remaining material includes other forms of the compound, and / or reaction impurities, and / or process impurities arising from its preparation. For example, a crystalline form of formula (I) may be considered substantially pure in that it has a purity of greater than 90% by weight, as measured by means currently known and generally accepted in the art, and the remaining less than 10% by weight of the material includes other forms of the compound of formula (I), and / or reaction impurities, and / or process impurities.

[0028] As used herein, "substantially phase pure", when used with respect to any crystalline form of the compound of formula (I), means a compound having a phase purity of greater than about 90% by weight of the compound (e.g., greater than about 90, 91, 92, 93, 94, 95, 96, 97, 98, and about 99% by weight, and about 100% by weight, based on the weight of the compound of formula (I) on an anhydrous basis. The term "phase pure" or "phase purity" as used herein refers to phase homogeneity with respect to a particular solid form of the compound of formula (I), and does not necessarily imply a high degree of chemical purity, unless expressly stated to that effect. For example, phase purity may be determined according to methods known in the art, using XRPD to perform quantitative phase analysis (e.g., by an external standard method, which is a direct comparison of the features of the lines (peaks) due to different phases in a particular spectrum, or by an internal standard method) using one or more approaches known in the art. However, XRPD quantification of phase purity can be complicated by the presence of non-crystalline material. Thus, other methods that may be useful for determining phase purity include, for example, solid-state NMR spectroscopy, Raman spectroscopy, and / or infrared spectroscopy. Those of skill in the art will readily understand these methods and how to use these additional (or alternative) methods to determine phase purity.

[0029] As used herein, "substantially chemically pure," when used in reference to any crystalline form of the compound of Formula (I), means a compound having a chemical purity of greater than about 90% by weight of the compound (e.g., greater than about 90, 91, 92, 93, 94, 95, 96, 97, 98, and about 99% by weight, and about 100% by weight, based on the weight of the compound of Formula (I) on an anhydrous basis. The remaining material will generally include other compounds (e.g., other stereoisomers of the compound of Formula (I)), reaction impurities, starting materials, reagents, by-products, and / or other processing impurities resulting from the preparation and / or isolation and / or purification of the particular crystalline form. For example, a crystalline form of the compound of formula (I) may be considered substantially chemically pure if it is determined to have a chemical purity of greater than about 90% by weight, as measured by standard and generally accepted methods known in the art, with the remaining less than about 10% by weight consisting of other substances (e.g., other stereoisomers of the compound of formula (I), reaction impurities, starting materials, reagents, by-products, and / or processing impurities). Chemical purity may 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.

[0030] As used herein, the term "seed" may be used as a noun to describe one or more crystals of the crystalline compound of formula (I). The term "seed" may also be used as a verb to describe the act of introducing said one or more crystals of the crystalline compound of formula (I) into an environment (such as, but not limited to, a solution, mixture, suspension, or dispersion), thereby resulting in the formation of more crystals or the growth of the introduced crystals of the crystalline compound of formula (I).

[0031] The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that elicits a biological or medical response in a subject, such as reducing or inhibiting the activity of an enzyme or protein, or ameliorating a symptom, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and / or ameliorate a condition, disorder, or disease that is (i) mediated by BTK, or (ii) associated with BTK activity, or (iii) characterized by activity (normal or abnormal) of BTK; or (2) reduce or inhibit the activity of BTK; or (3) reduce or inhibit the expression of BTK. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a cell, or tissue, or non-cellular biological material, or culture medium, is effective to at least partially reduce or inhibit the activity of BTK; or to partially or completely reduce or inhibit the expression of BTK.

[0032] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. Subjects include, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In a preferred embodiment, the subject is a human.

[0033] As used herein, a subject is "in need of" or "in need thereof" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0034] As used herein, the terms "a," "an," "the," and similar terms used in the context of the present invention (particularly in the context of the claims) are to be construed as encompassing both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0035] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to further clarify the invention and does not limit the scope of the invention unless otherwise asserted.

[0036] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0037] As used herein, the terms "treat", "treating", or "treatment" of any disease or disorder, in one embodiment, refer to ameliorating the disease or disorder (i.e., slowing or halting or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating", or "treatment" refers to reducing or ameliorating at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat", "treating", or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In one embodiment, "treat" or "treating" refers to slowing the worsening of the disease or disorder.

[0038] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or to delaying the onset of the disease or disorder.

[0039] The term "comprising" encompasses "including" and "consisting", e.g., a composition comprising X may consist solely of X or may include additional items (e.g., X and Y).

[0040] As used herein, the term "combination" refers to a fixed combination in one unit dosage form, or to combined administration in which the crystalline form of the compound of formula (I) and the combination partner (i.e., immunotherapeutic agent) can be administered simultaneously and independently or separately within a time interval, particularly one that allows the combination partners to exhibit a cooperative effect (e.g., synergistic effect). The single components can be packaged in a kit or packaged separately. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration.

[0041] The terms "co-administration" or "administration in combination" or the like, as used herein, are meant to encompass the administration of the selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0042] The terms "pharmaceutical combination" and "combination product" are used interchangeably and refer to a fixed combination in one unit dosage form, or to a non-fixed combination or kit of elements for combined administration, where two or more therapeutic agents can be administered simultaneously independently or separately within a time interval, in particular, where the time interval allows the combination partners to exhibit a cooperative effect (e.g., synergistic effect). The term "fixed combination" means that the crystalline form of the compound of formula (I) and the combination partner (i.e., immunotherapeutic agent) are both administered to the patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" means that the crystalline form of the compound of formula (I) and the combination partner (i.e., immunotherapeutic agent) are both administered to the patient as separate entities, simultaneously, concurrently, or consecutively without specific time limitations, such administration providing therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy (e.g., administration of three or more therapeutic agents). In a preferred embodiment, the pharmaceutical combination is a non-fixed combination.

[0043] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a BTK-related disease as described in this disclosure. Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as a single capsule with a fixed ratio of active ingredients. Alternatively, such administration includes co-administration in multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. The powders and / or liquids can be reconstituted or diluted to the desired dose before administration. In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner, either at about the same time or at different times. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the condition or disorder as described herein.

[0044] Crystalline form: The present disclosure relates to the anhydrous crystalline forms of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (compound of formula (I)) as described and characterized herein.

[0045] In one embodiment, the disclosure provides a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form A) having an X-ray powder diffraction (XRPD) pattern including a representative peak at 23.9±0.2 degrees 2θ (in terms of degrees 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 degrees 2θ, 18.3±0.2 degrees 2θ, and 23.4±0.2 degrees 2θ. In an aspect of the above embodiment, the XRPD pattern further comprises 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 measured at a temperature of about 25° C. In an aspect of the above embodiment, the XRPD pattern of crystalline Form A of the compound of Formula (I) can further comprise 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 measured at a temperature of about 25° C. Thus, the XRPD pattern of crystalline form A of compound of formula (I) when measured at a temperature of about 25° C. includes the following patterns: 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, 19.7±0.2° 2θ, 20.7±0.2° 2θ, 21.7±0.2° 2θ, 22.7±0.2° 2θ, 23.7±0.2° 2θ, 24.7±0.2° 2θ, 25.7±0.2° 2θ, 26.7±0.2° 2θ, 27.7±0.2° 2θ, 28.7±0.2° 2θ, 29.7±0.2° 2θ, 30.7±0.2° 2θ, 31.7±0.2° 2θ, 32.7±0.2° 2θ, 33.7±0.2° 2θ, 34.7±0.2° 2θ, 35.7±0.2° 2θ, 36.7±0.2° 2θ, 37.7±0.2° 2θ, 38.7±0.2° 2θ, 39.7±0.2° 2θ, 40.7±0.2° 2θ, 41.7±0.2° 2θ, 42.7±0.2° 2θ, 43.7±0.2° 2θ, θ, 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, 27.2±0.2°2θ, and 29.6±0.2°2θ. The XRPD pattern of crystalline form A can include one or more (e.g., 2, 3, 4, 5, or 6) representative peaks selected from the peaks disclosed in Table 1 and measured at a temperature of about 25° C.

[0046] In another aspect of the above embodiment, crystalline form A of compound of formula (I) has crystallinity of 7.8±0.2 degrees 2θ, 9.2±0.2 degrees 2θ, 12.0±0.2 degrees 2θ, 13.6±0.2 degrees 2θ, 15.6±0.2 degrees 2θ, 16.0±0.2 degrees 2θ, 17.8±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 18.7±0.2 degrees 2θ, 19.2±0.2 degrees 2θ, The compound is characterized by an X-ray powder diffraction pattern comprising four or more 2θ values ​​(CuKαλ=1.54184 Å) selected from the group consisting of 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, 27.2±0.2°2θ, and 29.6±0.2°2θ. In another aspect of the above embodiment, crystalline form A of compound of formula (I) has crystalline forms of 7.8±0.2 degrees 2θ, 9.2±0.2 degrees 2θ, 12.0±0.2 degrees 2θ, 13.6±0.2 degrees 2θ, 15.6±0.2 degrees 2θ, 16.0±0.2 degrees 2θ, 17.8±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 18.7±0.2 degrees 2θ, 19.2±0.2 degrees 2θ, 20.0±0.0° 2θ, 21.0±0.0° 2θ, 22.0±0.0° 2θ, 23.0±0.0° 2θ, 24.0±0.0° 2θ, 25.0±0.0° 2θ, 26.0±0.0° 2θ, 27.0±0.0° 2θ, 28.0±0.0° 2θ, 29.0±0.0° 2θ, 30.0±0.0° 2θ, 31.0±0.0° 2θ, 32.0±0.0° 2θ, 33.0±0.0° 2θ, 34.0±0.0° 2θ, 35.0±0.0° 2θ, 36.0±0.0° 2θ, 37.0±0.0° 2θ, 38.0±0.0° 2θ, 39.0±0.0° 2θ, 40.0±0.0° 2θ, 41.0±0.0° 2θ, 42.0±0.0° 2θ, 43.0±0.0° 2θ, 44.0±0.0° 2θ The compound is characterized by an X-ray powder diffraction pattern comprising five or more 2θ values ​​(CuKαλ=1.54184 Å) selected from the group consisting of 9.9±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, 27.2±0.2°2θ, and 29.6±0.2°2θ.

[0047] In yet another aspect of the above embodiment, crystalline form A of the compound of formula (I) has an XRPD pattern substantially as shown in FIG.

[0048] Crystalline form A of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide may be thermally characterized. In one embodiment, crystalline form A of the compound of formula (I) has a thermal profile measured by differential scanning calorimetry (DSC) with a heating rate of 10° C. / min, which includes a single endothermic peak with an onset at about 194° C. (corresponding to melting).

[0049] In another embodiment, crystalline Form A of the compound of formula (I) has a DSC thermogram substantially as shown in Figure 2. It should be understood that hydrated forms may produce different thermograms (in terms of peak shape and profile) depending on the instrumental parameters, such that the same material may have thermograms that appear substantially different from one another if the data is generated on two different instruments.

[0050] In another embodiment, crystalline Form A of the compound of formula (I) has a thermogravimetric analysis (TGA) diagram substantially identical to that shown in Figure 3. The weight loss by TGA is about 0.3% in the range of 40-200°C. Thermal decomposition occurred at 240°C.

[0051] In yet another embodiment, crystalline form A is substantially pure.

[0052] In yet another embodiment, crystalline form A is substantially chemically pure.

[0053] In yet another embodiment, crystalline form A is substantially phase pure.

[0054] In one embodiment, the present invention provides a method for preparing crystalline form A of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, comprising the steps of: a) reacting N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide with acrylic anhydride in a non-chlorinated solvent, optionally in the presence of an inorganic base; and b) isolating crystalline form A as a solid (e.g., by anti-solvent crystallization, cooling crystallization, distillation procedures, or evaporation of the solvent). The present invention relates to a method comprising the steps of:

[0055] In another embodiment, the present invention provides a method for preparing crystalline form A of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, comprising the steps of: (a) reacting N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide with acrylic anhydride in a non-chlorinated solvent, optionally in the presence of a base; (b) adding water to quench the reaction forming an aqueous phase and an organic phase; (c) separating the organic phase; (d) washing the organic phase with an acidic solution; and (e) isolating crystalline form A as a solid (e.g., by anti-solvent crystallization, cooling crystallization, a distillation procedure, or evaporation of the solvent). The present invention relates to a method comprising the steps of:

[0056] In one aspect of the previous two embodiments, step (a) of the method is carried out at a temperature of about 20° C. to about 65° C. Preferably, step (a) is carried out at a temperature of about 40° C. to about 65° C., and most preferably at a temperature of about 50° C.

[0057] In yet another aspect of the previous three embodiments, step (a) of the process is carried out in a non-chlorinated solvent selected from ethyl acetate and isopropyl acetate, preferably in ethyl acetate.

[0058] In yet another aspect of the previous four embodiments, step (a) is carried out in the presence of an inorganic base, preferably in the presence of a carbonate base, more preferably in the presence of sodium carbonate.

[0059] In another aspect of the above five embodiments, the method further comprises, after step (b) but before step (c), the step of stirring and heating the reaction mixture to a temperature of about 50° C. to about 65° C. and cooling to room temperature before step (c). This additional step can be useful to more efficiently remove the acrylic acid by-product.

[0060] In another aspect of the previous six embodiments, the acidic solution used in step (d) has a pH of about 1. For example, the acidic solution is a sulfuric acid solution (e.g., 0.05 M). The organic phase is washed with the acidic solution to remove the following by-products from the reaction mixture: [ka] Remove.

[0061] In yet another aspect of the previous seven embodiments, Form A is isolated as a solid by anti-solvent crystallization.Anti-solvent refers to a solvent in which the compound of formula (I) has low solubility (e.g., solubility less than 0.5 mg / mL, preferably solubility less than 0.25 mg / mL).Non-limiting examples of anti-solvents for use in this method are heptane, hexane, t-butyl methyl ether, toluene, or acetonitrile.

[0062] In further preferred aspects of the above seven embodiments, Form A is isolated as a solid by a distillation procedure.

[0063] The present invention also provides a process for preparing Form A of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, comprising the steps of: (a) suspending crystalline form B of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; or crystalline form C of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; or a mixture of forms B and C in a non-chlorinated solvent; and (b) isolating Form A as a solid (e.g., by anti-solvent crystallization, cooling crystallization, a distillation procedure, or evaporation of the solvent). Also provided is a method comprising:

[0064] The present invention also provides a process for preparing Form A of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, comprising the steps of: (a) suspending crystalline form B of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; or crystalline form C of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; or a mixture of forms B and C in a non-chlorinated solvent; and (b) equilibrating the suspension at room temperature for at least 2 weeks or equilibrating the suspension at 50° C. for at least 1 week; and (c) isolating Form A as a solid (e.g., by anti-solvent crystallization, cooling crystallization, a distillation procedure, or evaporation of the solvent). Also provided is a method comprising:

[0065] In one aspect of the previous two embodiments, the non-chlorinated solvent is selected from 1,4-dioxane, alcohol, acetone, acetonitrile, tetrahydrofuran, water, pyridine, nitromethane, anisole, alkyl acetate.

[0066] In yet another aspect of the previous three embodiments, crystalline form B, or crystalline form C, or a mixture thereof, may be dissolved in a non-chlorinated solvent. In such cases, isolating form A as a solid may involve anti-solvent crystallization, cooling crystallization, distillation procedures, or evaporation of the solvent. In other aspects, form B, form C, or a mixture thereof may remain in suspension, in which case form A is isolated by filtration.

[0067] The invention further provides a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form B) having an X-ray powder diffraction (XRPD) pattern including a representative peak at 20.9±0.2 degrees 2θ (in terms of degrees 2θ) when measured at a temperature of about 25° C. In another embodiment, the XRPD pattern further includes one or more additional representative peaks selected from 6.7±0.2 degrees 2θ, 11.1±0.2 degrees 2θ, 17.9±0.2 degrees 2θ, 20.2±0.2 degrees 2θ, 20.9±0.2 degrees 2θ, and 24.0±0.2 degrees 2θ when measured at a temperature of about 25° C. In an aspect of the above embodiment, the XRPD pattern of crystalline form B may further comprise 1, 2, 3, or 4 representative peaks selected from 5.9±0.2 degrees 2θ, 13.0±0.2 degrees 2θ, 14.8±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, and 22.6±0.2 degrees 2θ when measured at a temperature of about 25° C.

[0068] Therefore, the XRPD pattern of crystalline form B is 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, The XRPD pattern of crystalline form B may include one or more (e.g., 2, 3, 4, 5, or 6) representative peaks selected from 19.5±0.2°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. The XRPD pattern of crystalline form B may include one or more (e.g., 2, 3, 4, 5, or 6) representative peaks selected from the peaks disclosed in Table 2 and measured at a temperature of about 25° C. selected from the peaks disclosed in Table 2.

[0069] In another embodiment, the Form B has a viscosity of 5.9±0.2 degrees 2θ, 6.7±0.2 degrees 2θ, 7.8±0.2 degrees 2θ, 8.3±0.2 degrees 2θ, 11.1±0.2 degrees 2θ, 12.1±0.2 degrees 2θ, 12.6±0.2 degrees 2θ, 13.0±0.2 degrees 2θ, 13.3±0.2 degrees 2θ, 14.8±0.2 degrees 2θ, 15.8±0.2 degrees 2θ, 16.4±0.2 degrees 2θ, 17.6±0.2 degrees 2θ, The compound is characterized by an X-ray powder diffraction pattern comprising four or more 2θ values ​​(CuKαλ=1.54184 Å) selected from the group consisting of 19.5±0.2°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.

[0070] In another embodiment, the Form B has a viscosity of 5.9±0.2 degrees 2θ, 6.7±0.2 degrees 2θ, 7.8±0.2 degrees 2θ, 8.3±0.2 degrees 2θ, 11.1±0.2 degrees 2θ, 12.1±0.2 degrees 2θ, 12.6±0.2 degrees 2θ, 13.0±0.2 degrees 2θ, 13.3±0.2 degrees 2θ, 14.8±0.2 degrees 2θ, 15.8±0.2 degrees 2θ, 16.4±0.2 degrees 2θ, 17.6±0.2 degrees 2θ, The compound is characterized by an X-ray powder diffraction pattern comprising five or more 2θ values ​​(CuKαλ=1.54184 Å) selected from the group consisting of 19.5±0.2°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.

[0071] In yet another embodiment, crystalline form B of the compound of formula (I) has an XRPD pattern substantially as shown in FIG.

[0072] The crystalline form B of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide may be thermally characterized. In one embodiment, the crystalline form B of the compound of formula (I) has a differential thermogravimetric profile measured by DSC with a heating rate of 10° C. / min, comprising an endothermic peak with an onset at about 170° C. (corresponding to the melting of modification B), an exothermic peak with an onset at about 175° C. (corresponding to the recrystallization into modification A), and an exothermic peak with an onset at about 194° C. (corresponding to the melting of modification A).

[0073] In another embodiment, crystalline form B of the compound of formula (I) has a DSC thermogram substantially as shown in Figure 5. It should be understood that hydrated forms may produce different thermograms (in terms of peak shape and profile) depending on the instrumental parameters, such that the same material may have thermograms that appear substantially different from one another if the data is generated on two different instruments.

[0074] In another embodiment, crystalline form B of the compound of formula (I) has a thermogravimetric analysis (TGA) diagram substantially identical to that shown in Figure 6. The weight loss by TGA is about 0.2% in the range of 40-160°C. Thermal decomposition occurred above 240°C.

[0075] In yet another embodiment, crystalline form B is substantially pure.

[0076] In yet another embodiment, crystalline form B is substantially chemically pure.

[0077] In yet another embodiment, crystalline form B is substantially phase pure.

[0078] In one embodiment, the present invention provides a method for preparing crystalline form B of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, comprising the steps of: (a) suspending Form A in dichloromethane at a temperature of about 40° C. for about 3 days; (b) allowing the suspension to equilibrate at room temperature for about 5 days; and (c) isolating Form B as a solid (e.g., by filtration). The present invention relates to a method comprising the steps of:

[0079] In yet another embodiment, the present invention provides a method for preparing crystalline form B of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, comprising the steps of: a) suspending modification A in a solvent mixture comprising at least 50% by volume of dichloromethane; b) allowing the suspension to equilibrate at a temperature of about 50° C. for about two weeks; c) cooling the suspension to room temperature; and d) isolating the solid from the suspension (e.g., by filtration). The present invention relates to a method comprising the steps of:

[0080] In one aspect of the above embodiment, the solvent mixture is MeOH / dichloromethane 50:50 (v / v).

[0081] The present invention further provides a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form C) having an X-ray powder diffraction (XRPD) pattern including a representative peak at 5.9±0.2 degrees 2θ (in terms of degrees 2θ) when measured at a temperature of about 25° C. In another embodiment, the XRPD pattern further includes one or more additional representative peaks selected from 11.9±0.2 degrees 2θ, 17.0±0.2 degrees 2θ, and 19.3±0.2 degrees 2θ when measured at a temperature of about 25° C. In an aspect of the above embodiment, the XRPD pattern of crystalline form C may further comprise 1, 2, 3, or 4 representative peaks selected from 12.5±0.2 degrees 2θ, 15.3±0.2 degrees 2θ, 18.0±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.2±0.2 degrees 2θ, 23.4±0.2 degrees 2θ, and 23.7±0.2 degrees 2θ when measured at a temperature of about 25° C.

[0082] Therefore, the XRPD pattern of crystalline form C is 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, and 19.9±0.2°2θ. θ, 20.2±0.2°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. The XRPD pattern of crystalline form C can include one or more (e.g., 2, 3, 4, 5, or 6) representative peaks selected from the peaks disclosed in Table 3 and measured at a temperature of about 25° C. selected from the peaks disclosed in Table 3.

[0083] In another embodiment, the Form C has a viscosity of 5.9±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 12.0±0.2 degrees 2θ, 12.5±0.2 degrees 2θ, 12.9±0.2 degrees 2θ, 14.4±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, 15.3±0.2 degrees 2θ, 17.0±0.2 degrees 2θ, 18.0±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 19.2±0.2 degrees 2θ, 19.9±0.2 degrees 2θ, 19.2 ... 20.2±0.2°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 (CuKαλ=1.54184 Å).

[0084] In another embodiment, the Form C has a viscosity of 5.9±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 12.0±0.2 degrees 2θ, 12.5±0.2 degrees 2θ, 12.9±0.2 degrees 2θ, 14.4±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, 15.3±0.2 degrees 2θ, 17.0±0.2 degrees 2θ, 18.0±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 19.2±0.2 degrees 2θ, 19.9±0.2 degrees 2θ, 19.2 ... 20.2±0.2°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 (CuKαλ=1.54184 Å).

[0085] In yet another embodiment, the crystalline form C of the compound of formula (I) has an XRPD pattern substantially as shown in FIG.

[0086] The crystalline form C of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide may be characterized thermally. In one embodiment, the crystalline form C of the compound of formula (I) has a differential thermogravimetric profile measured by DSC with a heating rate of 10° C. / min, comprising a small exothermic peak between 90 and 120° C. (corresponding to the solid / solid transition from modification C to modification B), an endothermic peak with an onset at about 171° C. (corresponding to the melting of modification B), and an exothermic peak with an onset at about 175° C. (corresponding to the recrystallization into modification A), and an endothermic peak with an onset at about 195° C. (corresponding to the melting of modification A).

[0087] In another embodiment, crystalline Form C of the compound of formula (I) has a DSC thermogram substantially as shown in Figure 8. It should be understood that hydrated forms may produce different thermograms (in terms of peak shape and profile) depending on the instrumental parameters, such that the same material may have thermograms that appear substantially different from one another if the data is generated on two different instruments.

[0088] In another embodiment, crystalline form C has a thermogravimetric analysis (TGA) diagram substantially identical to that shown in Figure 9. The weight loss by TGA is about 0.01% in the range of 40-150°C. Thermal decomposition occurred above 240°C.

[0089] In yet another embodiment, crystalline form C is substantially pure.

[0090] In yet another embodiment, crystalline form C is chemically phase pure.

[0091] In yet another embodiment, crystalline form C is substantially phase pure.

[0092] In one embodiment, the present invention provides a method for preparing crystalline form C of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, comprising the steps of: a) suspending modification A in dichloromethane at a temperature of about 40° C. for about 3 days; b) cooling the suspension to room temperature; c) isolating Form C as a solid (e.g., by filtration). The present invention relates to a method comprising the steps of:

[0093] In another embodiment, the present invention provides a method for preparing crystalline form C of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, comprising the steps of: a) suspending modification A in a solvent mixture comprising at least 50% dichloromethane; b) allowing the suspension to equilibrate at room temperature for approximately 4 weeks; c) isolating Form C as a solid (e.g., by filtration). The present invention relates to a method comprising the steps of:

[0094] In one aspect of the above embodiment, the solvent mixture is MeOH / dichloromethane 50:50 (v / v).

[0095] In another embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form A, Form B, or a combination thereof) and at least one pharma- ceutically acceptable carrier, diluent, or excipient. In a particular embodiment, the present invention relates to a pharmaceutical composition comprising crystalline Form A and one or more pharma- ceutically acceptable carriers, diluents, or excipients. In yet another aspect, the present invention relates to a pharmaceutical composition comprising crystalline Form A in substantially phase-pure form. In yet another aspect, the present invention relates to a pharmaceutical composition comprising crystalline Form B in substantially phase-pure form. In yet another embodiment, the present 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-methylacrylamide)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-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

[0096] In another embodiment, the present invention relates to a combination (particularly a pharmaceutical combination) comprising a therapeutically effective amount of a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form A, Form B, or a combination thereof) and one or more therapeutic agents.

[0097] In a particular 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 phase 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 phase 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-methylacrylamide)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-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

[0098] In another embodiment, the present invention provides a pharmaceutical combination as described herein, wherein the therapeutic agent is independently selected from the group of immunosuppressants or immunomodulators, or other anti-inflammatory agents (e.g., anti-inflammatory agents for the treatment or prevention of acute or chronic rejection of allografts or xenografts, or inflammatory or autoimmune disorders), or chemotherapeutic agents (e.g., malignant cell anti-proliferative agents). For example, a crystalline form of the compound of formula (I) may be used in combination with calcineurin inhibitors, such as cyclosporin 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 Biolimus-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprine rene); methotrexate; leflunomide; mizoribine; mycophenolic acid or mycophenolate salts; mycophenolate mofetil; 15-deoxyspergualin or an immunosuppressant homologue, analogue or derivative thereof; PKC inhibitors, such as those disclosed in WO 02 / 38561 or WO 03 / 82859, such as the compounds of Examples 56 or 70;JAK3 kinase inhibitors, such as N-benzyl-3,4-dihydroxy-benzylidene-cyanoacetamide α-cyano-(3,4-dihydroxy)-]N-benzylcinnamamide (Tyrphostin AG 490), Prodigiosin 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-P 97, KRX-211, 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile in free form or in pharma- ceutically acceptable salt form (e.g., the monocitrate salt) (also referred to as CP-690,550), or the compounds disclosed in WO 04 / 052359 or WO 04 / 052359. compounds disclosed in WO 2005 / 066156; sphingosine-1-phosphate receptor modulators such as FTY720 (fingolimod), or compounds disclosed in WO 2005 / 000833; immunosuppressive monoclonal antibodies, such as monoclonal antibodies against leukocyte receptors (e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86) or their ligands; other immunomodulatory compounds, such as recombinant binding molecules having at least a portion of the extracellular domain of CTLA4 or variants thereof, e.g., at least the extracellular portion of CTLA4 or variants thereof linked to a non-CTLA4 protein sequence, e.g., CTLA4Ig (e.g., ATCC 61264 ... 68629) or a variant thereof, such as LEA29Y; an adhesion molecule inhibitor, such as an LFA-1 antagonist, an ICAM-1 antagonist or an ICAM-3 antagonist, a VCAM-4 antagonist, or a VLA-4 antagonist; or a chemotherapeutic agent, such as paclitaxel, gemcitabine, cisplatinum, doxorubicin, or 5-fluorouracil;or anti-infective agents. Further combination partners for the compounds of formula (I) may be selected from: PI3K inhibitors (e.g. pan, or alpha, beta, gamma, delta selective), TNF inhibitors, IL1 beta inhibitors, IL17 inhibitors, and inhibitors of the IL6 receptor or IL receptors.;

[0099] In one embodiment, the invention relates to a method of treating a disease or disorder in a subject in need thereof, typically ameliorated by inhibition of BTK, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form A, Form B, or a combination thereof, preferably Form A), alone or in combination with one or more therapeutic agents.

[0100] In another embodiment, the invention relates to a method of treating a disease or disorder that is typically ameliorated by inhibition of BTK (e.g., inflammatory and autoimmune disorders, and inflammation of the lungs and airways) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition described herein, alone or in combination with one or more therapeutic agents.

[0101] In another embodiment, the present invention relates to a method of treating a disease or disorder that is typically ameliorated by inhibition of BTK (e.g., inflammatory and autoimmune disorders, and inflammation of the lungs and airways) in a subject in need thereof, comprising administering to the subject a pharmaceutical combination described herein.

[0102] In one embodiment, the invention relates to the use of a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form A, Form B, or a combination thereof, preferably Form A), alone or in combination with one or more therapeutic agents, for the treatment of a disease or disorder that is typically ameliorated by inhibition of BTK (e.g., inflammatory and autoimmune disorders, and lung and airway inflammation).

[0103] In yet another embodiment, the present invention relates to a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form A, Form B, or a combination thereof, preferably Form A) for use in the treatment of a disease or disorder that is typically ameliorated by inhibition of BTK (e.g., inflammatory and autoimmune disorders, and inflammation of the lungs and airways).

[0104] In yet another embodiment, the present invention relates to a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form A, Form B, or a combination thereof, preferably Form A) in combination with one or more therapeutic agents for use in the treatment of a disease or disorder that is typically ameliorated by the inhibition of BTK.

[0105] In one embodiment, the invention relates to a method of treatment, use, compound for use, or combination for use as described herein, wherein the disease or disorder that is typically ameliorated by inhibition of BTK is selected from inflammatory and autoimmune disorders, and inflammation of the lungs and airways. More specifically, diseases or disorders that are typically ameliorated by inhibition of BTK are selected from the following: autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases in which antibody production, antigen presentation, cytokine production, or lymphoid tissue formation is abnormal or undesirable; such as rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic idiopathic urticaria, induced urticaria), chronic amyloidosis, and chronic urticaria. allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, B-cell mediated hyperacute, acute, and chronic graft rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism; cancers of the hematopoietic organs, 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; myelofibrosis with myeloid metaplasia; and Waldenstrom's disease. Preferably, the disease or disorder that is typically ameliorated by inhibition of BTK is selected from rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; Sjogren's syndrome, multiple sclerosis, or asthma.

[0106] Crystalline form A described herein has been found to have advantageous properties.

[0107] Form A of the compound of formula (I) is the most stable form. Form A was physically stable when exposed to high levels of %RH and during exposure to stress conditions over time. Form A is also stable in suspension in non-chlorinated solvents (e.g., solvents other than dichloromethane and chloroform).

[0108] Due to its non-hygroscopic behavior, the physicochemical properties of Form A of the present invention are preserved regardless of the relative humidity of the surrounding atmosphere, thus facilitating easier and more reliable manufacturing processes and easier storage of pharmaceutical products comprising said Form A. In addition, the crystalline Form A preserves its crystalline structure even when exposed to severe temperature and / or humidity stress conditions or when slurried in various solvents for extended periods of time.

[0109] The solvents chloroform and dichloromethane were found to result in the formation of modification B and / or modification C.

[0110] Modification C is a metastable form since it transforms into modification B at room temperature or upon heating at 50°C.

[0111] Modification B is stable up to 170°C, but above 170°C it transforms into modification A.

[0112] Pharmaceutical Compositions, Dosages, and Administration In one embodiment, the crystalline forms of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide described herein may be used alone or formulated into a pharmaceutical composition that also includes at least one pharma- ceutically acceptable excipient, and often includes at least two or more pharma-ceutically acceptable excipients. Some suitable excipients are disclosed herein. Other excipients known in the art may be used without departing from the spirit and scope of the present application.

[0113] In some embodiments, the present invention utilizes a pharmaceutical composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient.

[0114] As used herein, the term "pharmaceutical acceptable excipient" includes any and all solvents, carriers, diluents, dispersion media, coating agents, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents, antioxidants), isotonicity agents, absorption retardants, salts, drug stabilizers, binders, additives, fillers, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as would be known to one skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). It should be understood that the use of any conventional excipient in any therapeutic or pharmaceutical composition is contemplated by the present application, except insofar as such a conventional excipient is incompatible with the active ingredient.

[0115] The pharmaceutical compositions may be formulated for a particular route of administration, such as oral administration, parenteral administration, and rectal administration. In addition, the pharmaceutical compositions of the present invention may be prepared in solid form (such as, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (such as, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization, and / or may contain conventional inert diluents, lubricants, carriers, or buffers, as well as adjuvants (such as, for example, solvents, preservatives, stabilizers, wetting agents, emulsifiers, buffers, and the like).

[0116] Typically, the pharmaceutical composition is a tablet or capsule containing the active ingredient together with at least one excipient, which excipient may include: 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, c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; Also listed, if necessary, d) a carrier, e.g., an aqueous vehicle containing a cosolvating agent (e.g., captisol, PEG, glycerin, cyclodextrin, or the like); e) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or f) Absorbents, colouring agents, flavouring agents and sweeteners Examples include:

[0117] Tablets may be film coated or enteric coated according to methods known in the art.

[0118] Preferably, the compound or composition is prepared for oral administration (e.g., tablet or capsule), optionally packaged in a multi-dose format suitable for storage and / or administration of unit doses of pharmaceutical agent. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, unit dose containers (e.g., vials), blister packs, and strip packs.

[0119] Tablets may contain the active ingredient in a mixture with non-toxic pharma- ceutically acceptable excipients suitable for tablet manufacture.These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc.Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time.For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be provided 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 water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0120] The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can facilitate the degradation of certain compounds.

[0121] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture content ingredients and low moisture or low humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions are preferably packaged using materials known to prevent exposure to water so that the composition can be included in a suitable formulary kit. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0122] The present invention further provides pharmaceutical compositions and dosage forms that include one or more agents that reduce the rate at which the compounds of the present invention as an active ingredient will decompose. Such agents (referred to herein as "stabilizers") include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0123] The pharmaceutical composition or combination of the present invention may be a unit dosage of about 1-1000 mg of active ingredient, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient for a subject of about 50-70 kg. Preferably, the pharmaceutical composition or combination of the present invention may be a unit dosage of about 10 mg, about 25 mg, or about 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 of the subject, the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of the disorder or disease.

[0124] The dosage properties cited above are demonstrable by in vitro and in vivo tests, preferably using mammals (e.g. mice, rats, dogs, monkeys) or isolated organs, tissues and preparations thereof. The compounds of the invention can be applied in vitro in solutions (e.g., preferably in the form of an aqueous solution) and in vivo enterally, parenterally, advantageously intravenously, e.g., as a suspension or in an aqueous solution. The dosage in vitro is about 10 -3 Molar ~ 10 -9The therapeutically effective amount in vivo may range between about 0.1 and 500 mg / kg or about 1 and 100 mg / kg, depending on the route of administration. Preferably, the therapeutically effective amount in vivo is in the range of about 10 mg to about 200 mg per day, for example, about 10 mg, about 20 mg, about 25 mg, about 35 mg, about 50 mg, about 100 mg, or about 200 mg per day. Preferably, the therapeutically effective amount in vivo is selected from about 10 mg, about 35 mg, about 50 mg, or about 100 mg once per day. Similarly, preferably, the therapeutically effective amount in vivo is selected from about 10 mg, about 25 mg, about 50 mg, or about 100 mg twice per day.

[0125] In other embodiments, there is provided a pharmaceutical composition comprising at least one crystalline form (e.g., Form A, Form B, or a mixture thereof, preferably Form A) according to embodiments herein above, and at least one pharma- ceutically acceptable carrier.

[0126] Thus, in certain embodiments of the present disclosure, a crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form A or Form B, preferably Form A) is provided in substantially phase-pure form. This crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Form A or Form B) in substantially phase-pure form may be used to prepare a pharmaceutical composition, which may further include one or more pharma- ceutically acceptable excipients.

[0127] combination: The crystalline forms of the compound of formula (I) of the present invention (e.g., Form A or Form B, or a mixture thereof, preferably Form A) may be administered simultaneously with, prior to, or subsequent to one or more other therapeutic agents. The crystalline forms of the present invention may be administered separately by the same or different route of administration, or together with the other agents in the same pharmaceutical composition.

[0128] The crystalline forms of the compound of formula (I) may be administered as the sole active ingredient or together with other drugs (e.g., as an adjuvant to other drugs), such as immunosuppressants or immunomodulators, or other anti-inflammatory drugs (e.g., anti-inflammatory drugs for the treatment or prevention of acute or chronic rejection of allografts or xenografts, or inflammatory or autoimmune disorders), or chemotherapeutic drugs (e.g., malignant cell anti-proliferative drugs). For example, the crystalline forms of the compound of formula (I) may be used in combination with calcineurin inhibitors, such as cyclosporin 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 Biolimus-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or mycophenolate salts; mycophenolate mofetil; 15-deoxyspergualin, or an immunosuppressive homologue, analogue, or derivative thereof; PKC inhibitors, such as those disclosed in WO 02 / 38561 or WO 03 / 82859, such as the compound of Example 56 or 70;JAK3 kinase inhibitors, such as N-benzyl-3,4-dihydroxy-benzylidene-cyanoacetamide α-cyano-(3,4-dihydroxy)-]N-benzylcinnamamide (Tyrphostin AG 490), prodigiosin 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-P 97, KRX-211, 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile in free form or in pharma- ceutically acceptable salt form (e.g., the monocitrate salt) (also referred to as CP-690,550), or the compounds disclosed in WO 04 / 052359 or WO 04 / 052359. compounds disclosed in WO 2005 / 066156; sphingosine-1-phosphate receptor modulators such as FTY720 (fingolimod), or compounds disclosed in WO 2005 / 000833; immunosuppressive monoclonal antibodies, such as monoclonal antibodies against leukocyte receptors (e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86) or their ligands; other immunomodulatory compounds, such as recombinant binding molecules having at least a portion of the extracellular domain of CTLA4 or variants thereof, e.g., at least the extracellular portion of CTLA4 or variants thereof linked to a non-CTLA4 protein sequence, e.g., CTLA4Ig (e.g., ATCC 61264 ... 68629) or a variant thereof, such as LEA29Y; an adhesion molecule inhibitor, such as an LFA-1 antagonist, an ICAM-1 antagonist or an ICAM-3 antagonist, a VCAM-4 antagonist, or a VLA-4 antagonist; or a chemotherapeutic agent, such as paclitaxel, gemcitabine, cisplatinum, doxorubicin, or 5-fluorouracil;or anti-infective agents. Further combination partners for the compounds of formula (I) may be selected from: PI3K inhibitors (e.g. pan, or alpha, beta, gamma, delta selective), TNF inhibitors, IL1 beta inhibitors, IL17 inhibitors, and inhibitors of the IL6 receptor or IL receptors.;

[0129] Medical kit In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a crystalline form of compound of formula (I) (Form A, Form B, or a mixture thereof, preferably Form A). In one embodiment, the kit comprises a means for keeping said compositions separate, such as a container, a divided bottle, or a divided foil packet. One example of such a kit is a blister pack, such as those commonly used for packaging tablets, capsules, and the like.

[0130] The kits of the invention may be used to administer different dosage forms (e.g., oral and parenteral), to administer the separate compositions at different dosage intervals, or to titrate the separate compositions relative to one another. To aid in compliance, the kits of the invention typically include instructions for administration.

[0131] In the combination therapy of the present invention, the crystalline form of the compound of formula (I) (i.e., Form A, Form B, or a mixture thereof, preferably Form A) and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the crystalline form of the compound of formula (I) and the other therapeutic agent may be combined into a combination therapy (i) before the combination product is given to the physician (e.g., in the case of a kit containing the crystalline form of the compound of formula (I) and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) in the patient himself, e.g., during sequential administration of the crystalline form of the compound of formula (I) and the other therapeutic agent.

[0132] Thus, the present invention provides the use of a crystalline form described herein (i.e., Form A, Form B, or a mixture thereof, preferably Form A) to treat a disease ameliorated by inhibition of BTK (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases), where the agent is prepared for administration together with another therapeutic agent. The present invention also provides the use of a therapeutic agent to treat a disease ameliorated by inhibition of BTK (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases), where the agent is administered together with a crystalline form of the compound of Formula (I).

[0133] The present invention also provides a crystalline form of the compound of Formula (I) (i.e., Form A, Form B, or a mixture thereof, preferably Form A) for use in a method of treating a disease ameliorated by BTK inhibition, where the crystalline form of the compound of 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 ameliorated by BTK inhibition, where the other therapeutic agent is prepared for administration together with the crystalline form of the compound of Formula (I). The present invention also provides a crystalline form of the compound of Formula (I) for use in a method of treating a disease ameliorated by BTK inhibition, where the crystalline form of the compound of 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 ameliorated by BTK inhibition, where the other therapeutic agent is administered together with the crystalline form of the compound of Formula (I).

[0134] The invention also provides for the use of a crystalline form of the compound of formula (I) to treat a disease ameliorated by inhibition of BTK (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases), where the patient has already been treated (e.g., within 24 hours) with another therapeutic agent. The invention also provides for the use of a crystalline form of the compound of formula (I) to treat a disease ameliorated by inhibition of BTK (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases), where the patient has already been treated (e.g., within 24 hours) with another therapeutic agent.

[0135] Preparation of the crystalline form N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide: Crystalline forms can be prepared by a variety of methods, such as crystallization or recrystallization from a suitable solvent, sublimation, growth from the melt, solid-state conversion from another phase, crystallization from supercritical fluids, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent or solvent mixture include, for example, evaporation of the solvent, lowering the temperature of the solvent or solvent mixture, seeding a supersaturated solvent mixture of molecules and / or salts with crystals, freeze-drying the solvent mixture, and adding an anti-solvent (countersolvent) to the solvent mixture. Exemplary methods for preparing the crystalline forms described herein are described in detail below.

[0136] Drug crystals (including polymorphs), methods of preparation, and characterization of drug crystals are described in Solid-State Chemistry of Drugs, SR Byrn, RR Pfeiffer, and JG Stowell, 2002. nd Edition, SSCI, West Lafayette, Indiana (1999).

[0137] In the case of solvent-based crystallization techniques, the choice of solvent typically depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. A combination of solvents may be used, for example, a compound may be dissolved in a first solvent to obtain a solution, and then an anti-solvent may be added to reduce the solubility of the compound in this solution to form crystals. An anti-solvent is a solvent in which the compound has low solubility.

[0138] In one method of preparing crystals, the compound is suspended and / or slurried in a suitable solvent to obtain a slurry, which may be heated to promote dissolution. The term "slurry" as used herein means a saturated solution of a compound, which may also contain additional amounts of the compound, to obtain a heterogeneous mixture of the compound and the solvent at a given temperature. This is also referred to as a suspension.

[0139] Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be used to control the growth of a particular polymorph or to control the particle size distribution of the crystalline product. Thus, the calculation of the amount of seeds required depends on the available seed size and the desired size of the average product particle, as explained, for example, in "Programmed Cooling of Batch Crystallizers," JW Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small size seeds are required to effectively control the growth of crystals in a batch. Small size seeds may be generated by sieving, grinding, or micronizing larger crystals, or by microcrystallization of a solution. Care must be taken to ensure that grinding or micronizing the crystals does not cause a change in the crystallinity of the desired crystal form (i.e., to amorphous or another polymorph).

[0140] The cooled crystallization mixture can be filtered under vacuum, and the isolated solid can be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to obtain the desired crystalline form. The isolated solid can be analyzed by suitable spectroscopic or analytical techniques (e.g., solid-state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, or the like) to ensure the formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70% by weight isolated yield, and preferably greater than 90% by weight isolated yield, based on the weight of the compound originally used in the crystallization procedure. If necessary, the product can be co-ground or passed through a mesh screen to remove any clumps of the product.

[0141] Alternatively, the crystalline form may be prepared directly from the reaction medium of the final process for preparing N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. This may be achieved, for example, by using in the final process step a solvent or mixture of solvents from which N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide may be crystallized. In addition, the crystalline form may be obtained by distillation or solvent addition techniques.

[0142] It should be understood that a variety of analytical methods may be used to characterize any of the materials described herein, in addition to the methods briefly discussed below.

[0143] The following non-limiting examples are illustrative of the present disclosure. EXAMPLES

[0144] Example 1: Preparation of anhydrous crystalline form A [ka] N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (intermediate 10 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 minutes. After the addition of water, the reaction mixture was stirred at 65° C. for about 30 minutes. The phases were then separated at 60° C. and the aqueous phase was removed. The organic phase was washed with 0.05 M sulfuric acid and the aqueous phase was removed at 60° C. The organic phase was then washed with water and the aqueous phase was removed at 60° C. The final organic phase was treated by low particle filtration. At an internal temperature of 60° C., distillation was carried out under reduced pressure to remove a portion of the solvent mixture while simultaneously adding ethyl acetate to keep the solvent level approximately constant. This reduced the water content. (Optionally, a seed suspension of Form A in ethyl acetate is added to the solution). The suspension was stirred for at least 15 minutes. Then, a further distillation was carried out under reduced pressure at an internal temperature of 60° C. to remove a portion of the solvent mixture while simultaneously adding ethyl acetate to keep the solvent level approximately constant.

[0145] The suspension was stirred at 60° C. for 30 min, cooled to 30° C. in 200 min, and stirred at 30° C. for 30 min. At an internal temperature of 30° C., a final distillation was performed under reduced pressure with simultaneous addition of ethyl acetate to keep the solvent level approximately constant. After stirring at 30° C. for 120 min, the suspension was cooled to 0° C. in 300 min and stirred at 0° C. for at least 240. The product was isolated by centrifugation and the filter cake was washed twice with ethyl acetate. The isolated wet product was dried on a tray in a drying oven at 40° C. under vacuum. Crystalline form A was obtained. Modification A was characterized by HR-XRPD, LCMS, TGA, and DSC.

[0146] Example 2: Preparation of anhydrous crystalline form C Modification A (Example 1) was suspended in dichloromethane at 50° C. for 3 days. The suspension was then filtered through a Buchner filter. The solid was collected by filtration and dried overnight at room temperature under vacuum (200 mbar) to obtain modification C. Modification C was stored at −20° C. to prevent further changes.

[0147] Example 3: Preparation of anhydrous crystalline form B Modification C (Example 2) was left at room temperature and monitored by HR-XRPD for its transformation into modification B, which was complete after 5 days.

[0148] Modifications B and C were characterized by HR-XRPD, LCMS, TGA, and DSC.

[0149] Example 4: High-resolution powder X-ray diffraction The solid was finely ground in a mortar with a pestle. The compound was packed into an 8 mm boron glass capillary (0.3 mm diameter) and carefully placed in the diffractometer.

[0150] HR-XRPD patterns were collected at 296 K on a Bruker D8 Advance system equipped with a LynxEye solid-state detector. The radiation used to collect the data was CuKα1 (λ=1.54056 Å) monochromated by a germanium crystal. Diffraction data were collected in the range 4-50°2θ for modification A and 3-41.5°2θ for modifications B and C.

[0151] [Table 1]

[0152] [Table 2]

[0153] [Table 3]

[0154] Example 5: Differential Scanning Calorimetry (DSC) Melting characteristics were obtained from DSC thermograms and recorded on a heat flux DSC822e instrument (Mettler-Toledo GmbH, Switzerland). The DSC822e was calibrated for temperature and enthalpy by a small piece of indium (melting point 156.6°C; ΔH = 28.45 J / g). Samples were enclosed in standard 40 μl aluminum pans, pinhole punched or 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. Dry N2 at a flow rate of 50 ml / min was used during the measurements. 2 Gas was used to purge the DSC instrument.

[0155] Cyclic DSC was performed on the same instrument. Samples were sealed in standard 40 μl aluminum pans, pinhole drilled, heated in the DSC from 20° C. to 195° C., cooled from 195° C. to −20° C., and heated again from −20° C. to 300° C. The heating and cooling rates were 10° C. / min. The accuracy of the measured sample temperature by this method is within about ±1° C., and the heat of fusion can be measured within a relative error of about ±5%.

[0156] DSC measurements of modifications A, B, and C were carried out in open and sealed pans at various heating rates from −20 to 300° C.

[0157] The DSC traces recorded in an open pan for modifications A, B, and C are reported in Figures 2, 5, and 8, respectively. The onset temperatures of exothermic / endothermic events observed in the DSC traces are reported in Tables 4, 5, and 6, respectively.

[0158] In both sets of DSC measurements, a general shift of the thermal event to higher temperatures was observed with increasing heating rate, and a broadening of this event was also observed.

[0159] The DSC curves of modification A showed an onset melting temperature in the range 193-195 °C in open and closed pans, respectively. In the DSC measurements of modification B, an endothermic / exothermic event at 170-180 °C could be associated with the melting of modification B and its recrystallization to A.

[0160] In the DSC trace of modification C, the presence of an endothermic / thermal event at 170-180 °C confirmed that modification C was transformed into modification B upon heating.

[0161] [Table 4]

[0162] [Table 5]

[0163] [Table 6]

[0164] Example 6: Thermogravimetric Analysis (TGA): Mass loss due to loss of solvent or water from the crystals was determined by TGA / SDTA (single differential thermal analysis) and TGMS (thermogravimetric analysis coupled with mass spectrometry). Weight vs. temperature curves were obtained by monitoring the sample weight during heating in a TGA / DSC 3+ STARe system (Mettler-Toledo GmbH, Switzerland). The TGA / DSC 3+ was calibrated for temperature with samples of indium and aluminum. Samples (approximately 2 mg) were weighed into 100 μL aluminum crucibles and sealed. A pinhole was punched 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. Dry N 2Gas was used to purge the sample. The gases coming out of the TGA samples were analyzed with a mass spectrometer Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany). The latter is a quadrupole mass spectrometer that analyzes masses in the temperature range of 0 to 200 amu. Temperatures are reported in degrees Celsius (°C) and weight losses are reported in %.

[0165] TGA / SDTA analysis of modification A (Figure 3) revealed a mass loss of 0.3% in the range 40-200 °C, indicating that modification A was anhydrous. The endothermic peak around 190 °C in the SDTA curve could be attributed to melting of the compound. Thermal decomposition occurred above 240 °C.

[0166] Figure 3. TGA / SDTA analysis of modification A (heating rate of 10 °C / min). A mass loss of 0.3% was recorded in the range 40-200 °C. Thermal decomposition occurred above 240 °C.

[0167] TGA / SDTA analysis of modification B (Figure 6) revealed a mass loss of 0.2% in the range 40-160 °C. Modification B was therefore anhydrous. The events occurring in the SDTA curve above 160 °C are due to the melting of modification B and its recrystallization into modification A, followed by the final melting of modification A. Thermal decomposition occurred above 240 °C.

[0168] Figure 6. TGA / SDTA analysis of modification B (heating rate of 10 °C / min). A mass loss of 0.2% was recorded in the range 40-160 °C. Thermal decomposition occurred above 240 °C.

[0169] TGMS analysis of modification C (Figure 9) revealed a mass loss of 0.01% in the range 40–150 °C, indicating that modification C is an anhydrous crystalline phase. Thermal decomposition occurred above 240 °C.

[0170] Figure 9. TGA / SDTA (20A) and TGMS (20B) analysis of modification C (heating rate of 10 °C / min). A mass loss of 0.01% was recorded in the range 40-150 °C. Thermal decomposition occurred above 240 °C.

[0171] Example 4: Comparison of physicochemical stability Metamorphs A, B, and C were exposed to the following stress conditions: 80°C in a closed vial for 1 month; 80℃ / 75%RH in open vials for 1 month: 100°C in a closed vial for 3 days.

[0172] The solids were then analyzed by HR-XRPD, TGMS, and HPLC assays to assess potential solid-phase changes, loss on drying, and chemical purity.

[0173] Upon completion of the stability study, all solids were analyzed by HR-XRPD, TGMS, and HPLC assays. The results of the physicochemical stability studies are reported in Table 7.

[0174] HPLC conditions Auto sampler temperature: 15℃ Column: Waters Sunfire C18 (100 × 4.6 mm; 3.5 μm). Column temperature: 35℃ Flow cell: 10mm path Gradient: Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Flow rate: 1.0ml / min

[0175] [Table 7]

[0176] Run Time: 11 minutes

[0177] [Table 8]

[0178] After exposure to 80° C. for one month and to 100° C. for three days, modification C transformed into modification B. The XRPD patterns of modifications A and B did not change. In contrast, modification C transformed into modification B under all three tested conditions.

[0179] TGMS analysis did not show any significant moisture absorption, therefore the solid was not hygroscopic.

[0180] The chemical purity of the samples was not affected by exposure to high temperatures and high RH levels for either 3 days or 1 month, as indicated by recovery values ​​approaching 100%.

[0181] Example 5: Hygroscopicity test Moisture absorption of pervert A The hygroscopicity of modification A was evaluated by exposing the solid material to 80% and 92% RH at 25° C. for 24 hours. The solid was then analyzed by HT-XRPD to assess any changes in the crystalline phase and by TGMS to determine moisture uptake.

[0182] Modification A was physically stable after exposure to 80 and 92% RH for 24 h. TGMS analysis revealed a mass loss of 0.2% for both samples. Therefore, modification A could be considered non-hygroscopic.

[0183] Moisture sorption isotherms of modification A at 25°C and 40°C Dynamic Vapor Sorption (DVS): Moisture sorption isotherms were collected on a DVS-1 system from Surface Measurement Systems (London, UK). Typical sample size was 5-10 mg of solid material. The relative humidity profile was 40→0→95→0→95→40% with 10% RH level increase per step. Weight equilibration time was set at a minimum of 60 minutes and a maximum hold time of 6 hours per relative humidity step, with a dm / dt of 0.002% / min.

[0184] Dynamic vapor sorption (DVS) measurements were carried out on modification A at 25°C and 40°C with a RH profile of 40→0→95→0→95→40% in steps of 10% RH.

[0185] Modification A did not show significant water vapor uptake at both 25° C. and 40° C. At 95% RH, the highest mass changes were 0.4% and 0.3% at 25° C. and 40° C., respectively. The sorption and desorption cycles were reversible and DVS measurements gave no indication of hydrate formation. The solids recovered after DVS measurements remained as modification A.

[0186] DVS measurements of metamorphs B and C DVS measurements performed on modifications B and C gave results similar to those collected for modification A. Both crystalline phases did not show significant water vapor uptake. The highest mass gain recorded at 95% RH was 0.3% for both phases.

[0187] The XRPD pattern of modification B did not change after DVS measurement. In contrast, the solid recovered after DVS measurement of modification C was a mixture of modifications B and C, probably due to the spontaneous conversion of modification C to B at 25 °C.

[0188] Example 5: Stability in Solvents Stability of modification A in solvents Suspensions of modification A were prepared in 23 selected solvents and equilibrated at room temperature (RT) for 4 weeks and at 50° C. for 2 weeks. Upon completion of the equilibration period, the solid was separated from the liquid phase, dried under ambient conditions and under vacuum (5 mbar / 50° C.) and analyzed by HT-XRPD.

[0189] If the suspension dissolved, the solvent was removed by evaporation under vacuum (first at 200 mbar / RT, then at 5 mbar / 50° C.). The liquid phase was also evaporated under the same conditions. The remaining solid was analyzed by HT-XRPD.

[0190] Experimental details and results of solvent equilibration experiments performed at RT and 50° C. can be found in Tables 8 and 9, respectively.

[0191] [Table 9]

[0192] [Table 10]

[0193] Stability of modifications B and C in solvents Suspensions of modifications B and C were prepared in 15 selected solvents and equilibrated for 2 weeks at RT and for 1 week at 50° C. Upon completion of the equilibration period, the solids were separated from the liquid phase, dried under ambient conditions and under vacuum (5 mbar / 50° C.) and analyzed by HT-XRPD.

[0194] If the suspension dissolved, the solvent was removed by evaporation under vacuum (first at 200 mbar / RT, then at 5 mbar / 50° C.). The liquid phase was also evaporated under the same conditions. The remaining solid was analyzed by HT-XRPD.

[0195] The experimental details and results of the solvent equilibration experiments carried out at RT and 50° C. on modification B are reported in Tables 10 and 11, respectively.

[0196] The experimental details and results of the solvent equilibration experiments carried out at RT and 50° C. on modification C are reported in Tables 12 and 13, respectively.

[0197] [Table 11]

[0198] [Table 12]

[0199] [Table 13]

[0200] [Table 14]

[0201] Example 6: Stability under simulated granulation experiments Granulation solvent was added to polymorphic Form A until the solid was thoroughly wetted. The suspension was stirred with a Vortex between each addition. The suspension was dried under vacuum. The remaining solid form was isolated and analyzed for crystallinity by XRPD and / or DSC. Granulation solvents tested were water, ethanol, 2-propanol, acetone, and benzyl alcohol. No change in crystallinity was observed.

[0202] Example 7: Stability under compression 100-300 mg of polymorphic form A was compressed in a hydraulic press (plate diameter 13 mm) at 10 tons for 5 minutes. The samples were then analyzed by XRPD and DSC to confirm any polymorphic changes that had occurred. This analysis revealed no change in the material.

[0203] It has been discovered that modification A of compound of formula (I) is the most stable form. Modification A was physically stable when exposed to high levels of %RH and during exposure to prolonged stress conditions. Modification A was stable under compression and simulated granulation experiments. Modification A is stable in most solvents except for chlorinated solvents such as chloroform and dichloromethane or mixtures of solvents containing more than 50% by volume of chlorinated solvents (e.g., dichloromethane and / or chloroform).

[0204] Chlorinated solvents such as chloroform and dichloromethane induce the formation of modifications B and C. I realized that I would be woken up. Both modifications B and C are metastable forms, since modification C is stable at room temperature or at 50 When heated at 170°C, it changes to modification B, which changes to modification A at temperatures above 170°C. It is. The following aspects may be included. [1] When measured at a temperature of approximately 25°C and an X-ray wavelength λ of 1.5405 Å, the following values ​​are obtained: 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, 25.0±0.2°2θ, 26.0±0.2°2θ, 27.0±0.2°2θ, 28.0±0.2°2θ, 29.0±0.2°2θ, 30.0±0.2°2θ, 31.0±0.2°2θ, 32.0±0.2°2θ, 33.0±0.2°2θ, 34.0±0.2°2θ, 35.0±0.2°2θ, 36.0±0.2°2θ, 37.0±0.2°2θ, 38.0±0.2°2θ, 39.0±0.2°2θ, 40.0±0.2°2θ, 41.0±0.2°2θ, 42.0±0.2°2θ, 43.0±0.2°2θ, 44.0±0.2°2θ, 45.0±0.2°2θ, 46.0 20. A crystalline form of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, characterized by an X-ray powder diffraction pattern including one or more representative peaks at 2θ selected from the group consisting of 20.2°2θ, 25.2±0.2°2θ, 25.5±0.2°2θ, 27.2±0.2°2θ, and 29.6±0.2°2θ. [2] The crystalline form of [1] above, having an X-ray powder diffraction spectrum substantially identical to the X-ray diffraction spectrum shown in Figure 1. [3] The crystalline form described in [1] above, characterized in that a differential thermogravimetric profile measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min includes a single endothermic peak beginning at about 194°C. [4] The crystalline form described in [1] above, wherein the differential scanning calorimetry (DSC) thermogram is substantially identical to that shown in Figure 2. [5] The crystalline form of [1] above, having a decomposition point above 240°C and a weight loss on drying of about 0.3% in the range of 40-200°C, as determined by thermogravimetric analysis. [6] The crystalline form described in [1] above, whose thermogravimetric analysis (TGA) diagram is substantially identical to that shown in Figure 3. [7] The crystalline form according to any one of [1] to [6] above, essentially consisting of Form A. [8] The crystalline form according to any one of [1] to [6] above, wherein the form is Form A in a substantially phase-pure form. [9] Measured at a temperature of approximately 25°C and an X-ray wavelength λ of 1.5405 Å, the results are: 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. 20. A crystalline form of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, characterized by an X-ray powder diffraction pattern including one or more representative peaks at 2θ selected from the group consisting of 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.

[10] The crystalline form of [9] above, having an X-ray powder diffraction spectrum substantially identical to the X-ray diffraction spectrum shown in FIG.

[11] The crystalline form according to [9] above, characterized in that its differential thermogravimetric profile, measured by differential scanning calorimetry with a heating rate of 10°C / min, comprises an endothermic peak with an onset at about 170°C (corresponding to the melting of modification B), an exothermic peak with an onset at about 175°C (corresponding to the recrystallization into modification A) and an endothermic peak with an onset at about 194°C (corresponding to the melting of modification A).

[12] The crystalline form described in [9] above, whose differential scanning calorimetry (DSC) thermogram is substantially identical to that shown in Figure 5.

[13] The crystalline form of [9] above, having a decomposition point above 240°C and a weight loss on drying of about 0.2% in the range of 40-160°C, as determined by thermogravimetric analysis.

[14] A crystalline form as described in [9] above, having a thermogravimetric analysis (TGA) diagram substantially identical to that shown in Figure 6.

[15] The crystalline form according to any one of [9] to

[14] above, essentially consisting of form B.

[16] The crystalline form according to any one of [9] to

[14] above, wherein the form is Form B in a substantially phase pure form.

[17] A pharmaceutical composition comprising the crystalline form described in [1] above and a pharma- ceutically acceptable carrier.

[18] A pharmaceutical composition comprising the crystalline form described in [9] above and a pharma- ceutically acceptable carrier.

[19] Use of a substantially phase-pure crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide according to any one of the above [1] to

[16] for the preparation of a medicament for the treatment of a disorder that is ameliorated by inhibition of BTK.

[20] A method for treating a disorder ameliorated by inhibition of BTK, comprising administering to a patient in need of such treatment an effective amount of a substantially phase-pure crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide described in any one of [1] to

[16] above.

[21] Disorders that may be ameliorated by inhibition of BTK include autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, e.g., asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases in which antibody production, antigen presentation, cytokine production, or lymphoid tissue formation is abnormal or undesirable; e.g., rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic idiopathic 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, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, B-cell mediated hyperacute, acute and chronic graft rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism; cancers of hematopoietic organs, 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; myelofibrosis with myeloid metaplasia; and Waldenstrom's disease. Preferably, the disease or disorder that is typically ameliorated by inhibition of BTK is selected from rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; Sjogren's syndrome, multiple sclerosis, or asthma.

[22] A method for preparing crystalline form A of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, comprising: a) reacting N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide with acrylic anhydride in a non-chlorinated solvent, optionally in the presence of an inorganic base; and b) isolating crystalline form A as a solid (e.g., by anti-solvent crystallization, cooling crystallization, distillation procedures, or evaporation of the solvent). The method includes:

[23] The method for preparing crystalline form A according to

[22] above, wherein the non-chlorinated solvent is ethyl acetate.

[24] The method for preparing crystalline form A according to

[22] or

[23] above, wherein form A is isolated by distillation.

Claims

1. A polymorph of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, characterized by an X-ray powder diffraction pattern with representative peaks at 2θ of the following: 7.8±0.2 degrees 2θ, 9.2±0.2 degrees 2θ, and 12.0±0.2 degrees 2θ, when measured at a temperature of about 25° C. and an X-ray wavelength λ of 1.5405 Å, where the term "about" indicates a variation of ±5%.

2. The polymorph of claim 1, further characterized by the following additional representative peaks when measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5405 Å: 18.3±0.2°2θ, and 23.9±0.2°2θ, where the term "about" indicates a variation of ±5%.

3. The polymorph of claim 2, 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 about 25° C. and an X-ray wavelength λ of 1.5405 Å.

4. Figure 1 below 【Table 1】 4. The polymorph of any one of claims 1 to 3, having an X-ray diffraction spectrum shown in Figure 3 with variation in peak positions (2θ) of up to ±0.2°.

5. 4. The polymorph of any one of claims 1 to 3, characterized in that the differential thermogravimetric profile measured by Differential Scanning Calorimetry (DSC) at a heating rate of 10°C / min comprises a single endothermic peak with an onset at about 194°C, the term "about" indicating a variation of ±5%.

6. Figure 2 below 【Table 2】 4. The polymorph of any one of claims 1 to 3, having a Differential Scanning Calorimetry (DSC) thermogram as shown in Figure 3 with up to ±5°C variation in endotherm / melting point value.

7. 4. The polymorph of any one of claims 1 to 3, having a decomposition point above 240°C and a weight loss on drying of about 0.3% in the range of 40-200°C, the term "about" indicating a variation of ±5%, as determined by thermogravimetric analysis.

8. Figure 3 below 【Table 3】 4. The polymorph of any one of claims 1 to 3, having a thermogravimetric analysis (TGA) diagram as shown in

9. The polymorph of any one of claims 1 to 8 having a purity of greater than 90% by weight.

10. A pharmaceutical composition comprising the polymorph of any one of claims 1 to 9 and a pharma- ceutically acceptable carrier, in solid form.

11. Use of a polymorph of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide according to any one of claims 1 to 9 for the preparation of a medicament for the treatment of a disorder ameliorated by inhibition of BTK.

12. 10. A pharmaceutical composition in solid form for use in a method of treating a disorder ameliorated by inhibition of BTK, said pharmaceutical composition comprising a polymorph of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide according to any one of claims 1 to 9, said method comprising administering to a patient in need of such treatment an effective amount of said polymorph of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

13. The disorders that are ameliorated by inhibition of BTK include autoimmune disorders, inflammatory diseases, allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), transplant rejection; rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria, atopic dermatitis, contact dermatitis, allergic rhinitis, atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, and the like.

13. The pharmaceutical composition for use according to claim 12, wherein the disease is selected from the group consisting of pulmonary graft rejection, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, B-cell mediated hyperacute, acute and chronic graft rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism; multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom's disease.

14. 13. The pharmaceutical composition for use according to claim 12, wherein the disease ameliorated by inhibition of BTK is selected from rheumatoid arthritis; chronic urticaria; Sjogren's syndrome, multiple sclerosis, or asthma.

15. 15. The pharmaceutical composition for use according to claim 14, wherein the chronic urticaria is chronic idiopathic urticaria or provoked urticaria.

16. A process for preparing a polymorph of the compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide according to any one of claims 1 to 9, comprising the steps of: a) reacting N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide with acrylic anhydride in a non-chlorinated solvent, optionally in the presence of an inorganic base; and b) isolating said polymorph by anti-solvent crystallization, cooling crystallization, distillation procedures, or evaporation of the solvent. The method includes:

17. 17. A method for making the polymorph of claim 16, comprising reacting N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide with acrylic anhydride in a non-chlorinated solvent in the presence of an inorganic base.

18. 18. A method for making the polymorph of claim 17, wherein said inorganic base is sodium carbonate.

19. 19. A method for preparing the polymorph of any one of claims 16 to 18, wherein the non-chlorinated solvent is ethyl acetate.

20. A process for preparing the polymorph of any one of claims 16 to 19, wherein the polymorph is isolated by distillation.

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