Crystalline forms of BTK inhibitor

Abstract

The present application relates to a plurality of anhydrous crystal forms of N-(3-(6-amino-5-(2-(N-methacrylamido) ethyoxyl) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, as well as compositions, methods of preparation and methods of use thereof. These crystalline forms are useful in the treatment of diseases and disorders that are typically ameliorated by inhibition of BTK. Such diseases and disorders may include inflammation and autoimmune disorders as well as lung and respiratory tract inflammation.

Description

[0001] This application is a divisional application of Chinese invention patent application No. 202080036320.6, filed on May 20, 2020, entitled "Crystal Form of BTK Inhibitor". Technical Field

[0002] This disclosure involves N- (3-(6-amino-5-(2-( N- The crystalline form of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. This disclosure also relates to pharmaceutical compositions comprising said crystalline form, methods for obtaining such crystalline forms, and methods for using such crystalline forms in the treatment of diseases and disorders typically improved by inhibiting Bruton's tyrosine kinase. Such diseases and disorders may include inflammatory and autoimmune disorders, as well as inflammation of the lungs and respiratory tract. Background Technology

[0003] Polymorphism means that a substance has more than one crystal form.

[0004] The solid form of the active pharmaceutical ingredient (API) of a particular drug is often a crucial determinant of its ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in vivo. Crystal forms arise where the same composition of substances crystallizes in different lattice arrangements, leading to different thermodynamic properties and stability specific to a particular crystal form. Crystal forms can also include different hydrates or solvates of the same compound. In determining which form is preferred, many characteristics of the forms are compared, and the preferred form is selected based on many physical property variables. It is entirely possible that in some cases, certain aspects such as ease of preparation and stability are considered crucial, and one form may be preferred. In other cases, different forms may be preferred for greater dissolution rates and / or superior bioavailability.

[0005] Therefore, the ability of chemical substances to crystallize in more than one crystalline form can profoundly influence a drug's shelf life, solubility, formulation properties, and processing characteristics. Furthermore, drug efficacy can be affected by drug molecular polymorphism. Different polymorphs can have different uptake rates in vivo, resulting in lower or higher biological activity than desired. In extreme cases, undesirable polymorphs may even exhibit toxicity. The occurrence of unknown crystalline forms during manufacturing can have significant implications.

[0006] It is not possible to predict whether a particular compound or its salt will form a polymorph, whether any such polymorph will be suitable for commercial use in a therapeutic composition, or which polymorph will exhibit such desirable properties. However, in some cases, knowing which crystal forms of a drug are possible allows researchers to maximize the desired properties of a compound, such as solubility, formulation properties, processing characteristics, and shelf life. Understanding these factors early in new drug development may mean more active, more stable, or cheaper drugs.

[0007] Therefore, a solid form is required. N- (3-(6-amino-5-(2-( N- Methacrylamide (ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, having physicochemical properties that allow for the reliable and safe production of effective pharmaceutical products, said pharmaceutical products comprising... N- (3-(6-amino-5-(2-( N- Methacrylamide (ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

[0008] In Example 6 N- (3-(6-amino-5-(2-( N- Methacrylamide (ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide was first disclosed in WO 2015 / 079417, filed on 28 November 2014, which is incorporated herein by reference in its entirety. N- (3-(6-amino-5-(2-( N- Methacrylamide (ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is a Bruton's tyrosine kinase (BTK) inhibitor having the structure of formula (I): Formula (I) However, WO 2015 / 079417 did not provide any information regarding... N- (3-(6-amino-5-(2-( N- Information on the crystal forms of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. It has been discovered... N- (3-(6-amino-5-(2-( N-The crystalline form of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is used to treat diseases typically improved by inhibiting BTK. These diseases and conditions include inflammation and autoimmune disorders, as well as inflammation of the lungs and respiratory tract. Summary of the Invention

[0009] In one aspect, the present invention provides a form in which the substance is free (i.e., in a non-salt form). N- (3-(6-amino-5-(2-( N- Three crystal forms of methacrylamide (methacrylamido)ethoxypyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. In a specific embodiment, the free form is the anhydrous form of the compound having formula (I).

[0010] Examples of these crystal forms include those designated herein as Type A, Type B, and Type C. The names used herein to identify a particular form (e.g., “Type A”, “Type B”, or “Type C”) should not be considered as limitations on any other substance having similar or identical physical and chemical characteristics, but rather should be understood as identifiers to be interpreted solely based on the characteristic information also presented herein.

[0011] In one aspect, the present invention also provides a pharmaceutical composition comprising: (a) a therapeutically effective amount N- (3-(6-amino-5-(2-( N- (a) a crystalline form A of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; and (b) at least one pharmaceutically 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 N- (3-(6-amino-5-(2-( N- (a) a crystalline form B of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; and (b) at least one pharmaceutically 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 methods for preparing N- (3-(6-amino-5-(2-( N-A method for obtaining crystal form A of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: a) will N -(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and acrylic anhydride are reacted in a non-chlorinated solvent, optionally in the presence of an inorganic base; and b) Separate the solid crystal form A (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

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

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

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

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

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

[0020] Therefore, the crystal form of the compound having formula (I) as described herein can be used to treat the following diseases or disorders mediated by or improved by BTK inhibition: 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 organogenesis is abnormal or undesirable; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura. Vitiligo, 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 spontaneous urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease (Morbus syndrome) Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism; hematopoietic cancers, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenstrom's disease.

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

[0022] project 1. Compound N- (3-(6-amino-5-(2-( N-A crystalline form of methacrylamide (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, characterized by the following X-ray powder diffraction pattern, which, when measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5405 Å, contains one or more representative peaks, which, in terms of 2θ, are selected from the group consisting of: 7.8 ± 0.2 °2θ, 9.2 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 13.6 ± 0.2 °2θ, 15.6 ± 0.2 °2θ, 16.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 22.1 ± 0.2 °2θ, 23.4± 0.2 °2θ, 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.

[0023] 2. According to the crystal form described in Project 1, the crystal form has the same properties as... Figure 1 The X-ray powder diffraction patterns shown are essentially the same as the X-ray diffraction patterns.

[0024] 3. The crystal form according to Item 1, characterized by a differential thermogravimetric curve measured by differential scanning calorimetry (DSC) at a heating rate of 10 °C / min, the curve containing a single endothermic peak starting at approximately 194 °C.

[0025] 4. According to the crystal form described in Project 1, the crystal form has the same properties as... Figure 2 The figures shown are essentially the same differential scanning calorimetry (DSC) thermal analysis graphs.

[0026] 5. The crystal form according to Item 1, wherein the crystal form has a decomposition point greater than 240°C and a drying loss of approximately 0.3% in the range of 40°C to 200°C, as determined by thermogravimetric analysis.

[0027] 6. The crystal form according to Project 1, wherein the crystal form has the same properties as... Figure 3 The figures shown are essentially the same as the thermogravimetric analysis (TGA) figures.

[0028] 7. The crystal form according to any one of items 1 to 6 is essentially composed of type A.

[0029] 8. The crystal form according to any one of items 1 to 6, wherein the crystal form is type A in a substantially phase-pure form.

[0030] 9. Compounds N- (3-(6-amino-5-(2-( N- A crystalline form of methacrylamide (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, characterized by the following X-ray powder diffraction pattern, measured at a temperature of about 25 °C and an X-ray wavelength λ of 1.5405 Å, said diffraction pattern containing one or more representative peaks, which, in terms of 2θ, are selected from the group consisting of: 5.9 ± 0.2 °2θ, 6.7 ± 0.2 °2θ, 7.8 ± 0.2 °2θ, 8.3 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 12.1 ± 0.2 °2θ, 12.6 ± 0.2 °2θ, 13.0 ± 0.2 °2θ, 13.3 ± 0.2 °2θ, 14.8 ± 0.2 °2θ, 15.8 ± 0.2 °2θ, 16.4 ± 0.2 °2θ, 17.6 ± 0.2 °2θ, 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.

[0031] 10. The crystal form according to item 9, wherein the crystal form has the same properties as... Figure 4 The X-ray powder diffraction patterns shown are essentially the same as the X-ray diffraction patterns.

[0032] 11. The crystal form according to item 9, characterized by a differential thermogravimetric curve measured by differential scanning calorimetry at a heating rate of 10 °C / min, the curve including an endothermic peak starting at about 170 °C (corresponding to the melting of variant B), an exothermic peak starting at about 175 °C (corresponding to recrystallization to variant A), and an endothermic peak starting at about 194 °C (corresponding to the melting of variant A).

[0033] 12. The crystal form according to item 9, wherein the crystal form has the same properties as... Figure 5 The figures shown are essentially the same differential scanning calorimetry (DSC) thermal analysis graphs.

[0034] 13. The crystal form according to Item 9, wherein the crystal form has a decomposition point greater than 240°C and a drying loss of approximately 0.2% in the range of 40°C to 160°C, as determined by thermogravimetric analysis.

[0035] 14. The crystal form according to item 9, wherein the crystal form has the same properties as... Figure 6 The figures shown are essentially the same as the thermogravimetric analysis (TGA) figures.

[0036] 15. The crystal form according to any one of items 9 to 14 is substantially composed of type B.

[0037] 16. The crystal form according to any one of items 9 to 14, wherein the crystal form is type B in a substantially phase-pure form.

[0038] 17. A pharmaceutical composition comprising the crystal form according to item 1 and a pharmaceutically acceptable carrier.

[0039] 18. A pharmaceutical composition comprising the crystal form according to item 9 and a pharmaceutically acceptable carrier.

[0040] 19. According to any one of items 1 to 16 N- (3-(6-amino-5-(2-( N- The substantially phase-pure crystalline form of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is used for the preparation of a medicament for treating a disorder that is improved by inhibiting BTK.

[0041] 20. A method for treating a disorder that is improved by inhibiting BTK, the method comprising administering to a patient requiring such treatment an effective amount of any one of claims 1 to 16. N- (3-(6-amino-5-(2-( N- The essentially phase-pure crystalline form of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

[0042] 21. The method described in Item 20 or the use described in Item 19, wherein the disorder improved by inhibiting BTK is selected from autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; wherein antibody production, antigen presentation, cytokine production, or lymphoid organogenesis is abnormal or undesirable; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic spontaneous urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 Type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasser syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism; hematopoietic cancers, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenstrom disease; preferably, diseases or disorders typically improved by BTK inhibition are selected from rheumatoid arthritis; chronic urticaria, preferably chronic spontaneous urticaria; Sjögren's syndrome, multiple sclerosis, or asthma.

[0043] 22. A method for preparing compounds N- (3-(6-amino-5-(2-( N- A method for obtaining crystal form A of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: a) will N -(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and acrylic anhydride are reacted in a non-chlorinated solvent, optionally in the presence of an inorganic base; and b) Separate the solid crystal form A (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

[0044] 23. The method for preparing crystal form A according to item 22, wherein the non-chlorinated solvent is ethyl acetate.

[0045] 24. The method for preparing crystal form A according to item 22 or 23, wherein form A is separated by distillation. Attached Figure Description

[0046] Figure 1 Illustrative XRPD spectra of the crystal-agnostic form (designated as type A herein) of the compound having formula (I) are provided, showing 2θ (2-θ) degrees on the X-axis and relative intensities on the Y-axis.

[0047] Figure 2 An illustrative DSC is provided for the crystal-amorphous form (designated as type A herein) of compounds having formula (I).

[0048] Figure 3 An illustrative TGA is provided for the crystal-amorphous form (designated as type A herein) of compounds having formula (I).

[0049] Figure 4 Illustrative XRPD spectra of the crystal-amorphous form (designated as type B herein) of the compound having formula (I) are provided, showing 2θ (2-θ) degrees on the X-axis and relative intensities on the Y-axis.

[0050] Figure 5 An illustrative DSC is provided for the crystal-amorphous form (designated as type B herein) of the compound having formula (I).

[0051] Figure 6 An illustrative TGA is provided for the crystal-amorphous form (designated as type B herein) of compounds having formula (I).

[0052] Figure 7 Illustrative XRPD spectra of the crystal-agnostic form (designated as type C herein) of the compound having formula (I) are provided, showing 2θ (2-θ) degrees on the X-axis and relative intensities on the Y-axis.

[0053] Figure 8 An illustrative DSC is provided for the crystal-amorphous form (designated as type C herein) of compounds having formula (I).

[0054] Figure 9 An illustrative TGA is provided for the crystal-amorphous form (designated as type C herein) of compounds having formula (I).

[0055] Tables 1 and 2 below provide a more detailed list of XRPD peaks for each of types A, B, and C, respectively, with relative intensity % (I / I0 x 100) also provided. It should be understood that inherent variability exists in values ​​measured at 2θ degrees (°2θ) in X-ray powder diffraction spectra or X-ray powder diffraction patterns due to, for example, instrument variations (including differences between instruments). Similarly, it should be understood that variability of up to ±0.2 °2θ exists in XRPD peak measurements; however, such peaks will still be considered representative of the specific solid-state form of the crystalline material described herein. It should also be understood that other measurements from XRPD and DSC / TGA experiments (such as relative intensity and water content) may vary due to, for example, sample preparation and / or storage and / or environmental conditions; however, these measurements will still be considered representative of the specific solid-state form of the crystalline material described herein. Detailed Implementation

[0056] definition As used herein, the terms “about” and “substantially” indicate that their values ​​can vary for characteristics such as endothermic, endothermic peaks, exothermic, baseline shifts, etc. Regarding X-ray diffraction peak positions, “about” or “substantially” means taking into account typical peak position and intensity variability. For example, those skilled in the art will understand that peak positions (2θ) can show variability between certain devices, typically up to 0.2°. Occasionally, variability may be greater than 0.2°, depending on differences in device calibration. Furthermore, those skilled in the art will understand that relative peak intensities will show variability between devices as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be used only as qualitative measurements. For DSC, the observed temperature variation will depend on the rate of temperature change and the sample preparation technique and the specific instrument used. Therefore, the endothermic / melting point values ​​reported herein for DSC / TGA thermal analysis plots can vary by ±5°C (and are still considered characteristic of the specific crystal form described herein). When used in the context of other characteristics such as weight percentage (by weight%), reaction temperature, the term “about” indicates a variance of ±5%.

[0057] The terms “one or more crystal forms” or “one or more crystal variants” or “one or more polymorphs” or “one or more polymorphs” will be used interchangeably throughout this document. As used herein, “polymorph” refers to a crystal form having the same chemical composition but different spatial arrangements of molecules, atoms, and / or ions that form crystals. Each polymorph differs in thermodynamic stability, physical parameters, X-ray structure, and preparation method.

[0058] As used herein, "amorphous" refers to a solid form that is not a crystal, consisting of molecules, atoms, and / or ions. Amorphous solids do not exhibit defined X-ray diffraction patterns.

[0059] As used herein, when referring to a form, "substantially pure" means a compound having a purity greater than 90% by weight, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, and also including a purity of approximately 100% by weight of a compound having formula (I). The remaining material comprises one or more other forms of the compound, and / or reactive impurities and / or processing impurities arising from its preparation. For example, a crystal form of a compound having formula (I) may be considered substantially pure because it has a purity greater than 90% by weight as measured by means known and generally accepted in the art at this time, wherein the remaining less than 10% by weight of the material comprises one or more other forms of the compound having formula (I) and / or reactive impurities and / or processing impurities.

[0060] As used herein, when referring to any crystal form of a compound having formula (I), "substantially phase-pure" means a compound having a phase purity of more than about 90% by weight based on the weight of the compound (on anhydrous basis), including more than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and about 99% by weight, and also including a phase purity of about 100% by weight of the compound having formula (I). The terms "phase-pure" or "phase purity" herein refer to the phase homogeneity of a particular solid form of a compound having formula (I) and do not necessarily imply a high degree of chemical purity in the absence of an explicit statement thereof. Phase purity can be determined according to methods known in the art, for example, quantitative phase analysis using XRPD with one or more methods known in the art, such as by external standard method, direct comparison of line (peak) characteristics (attributed to different phases in a particular spectrum), or by internal standard method. However, the presence of amorphous materials can complicate the XRPD quantification of phase purity. Therefore, other methods that can be used to determine phase purity include, for example, solid-state NMR spectroscopy, Raman and / or infrared spectroscopy. Those skilled in the art will readily understand these methods, and how to employ these additional (or alternative) methods to determine phase purity.

[0061] As used herein, when referring to any crystal form of a compound having formula (I), "substantially chemically pure" means a compound having a chemical purity of more than about 90% by weight based on the weight of the compound (on anhydrous basis), including more than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and about 99% by weight, and also including a chemical purity of about 100% by weight of the compound having formula (I). The remaining material typically includes other compounds (e.g., other stereoisomers of compounds having formula (I), reaction impurities, starting materials, reagents, byproducts, and / or other processing impurities arising from the preparation and / or isolation and / or purification of a particular crystal form. For example, if a compound having formula (I) has been determined to have a chemical purity of more than about 90% by weight, as measured by standards and generally accepted methods known in the art, it can be considered substantially chemically pure, wherein the remaining less than about 10% by weight constitutes other materials, such as other stereoisomers of the compound having formula (I), reaction impurities, starting materials, reagents, byproducts, and / or processing impurities. Chemical purity can be determined according to methods known in the art, such as high-performance liquid chromatography (HPLC), LC-MS (liquid chromatography-mass spectrometry), nuclear magnetic resonance (NMR) spectroscopy, or infrared spectroscopy. Those skilled in the art will readily understand these methods, and how these additional (or alternative) methods can be used to determine chemical purity.

[0062] As used herein, the term "seed" can be used as a noun to describe one or more crystals of a crystalline compound having formula (I). The term "seed" can also be used as a verb to describe the act of introducing one or more crystals of the crystalline compound having formula (I) into an environment (including, but not limited to, a solution, mixture, suspension, or dispersion) resulting in the formation of more crystals of the crystalline compound having formula (I) or the growth of introduced crystals of the crystalline compound having formula (I).

[0063] The term "therapeuticly effective amount" for the compounds of the present invention refers to an amount of the compound of the present invention that will elicit a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or relief of symptoms, symptom relief, slowing or delaying disease progression, or prevention of disease, etc.). In one non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of the present invention that, when administered to a subject, effectively (1) at least partially relieves, inhibits, prevents, and / or improves (i) a symptom, disorder, or disease mediated by BTK, or (ii) associated with BTK activity, or (iii) characterized by (normal or abnormal) BTK activity; or (2) reduces or inhibits BTK activity; or (3) reduces or inhibits BTK expression. In another non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of the present invention that, when applied to cells, or tissues, or non-cellular biological materials, or media, effectively reduces or inhibits BTK activity at least partially; or partially or completely reduces or inhibits BTK expression.

[0064] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. Subjects include, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the subject is a human.

[0065] As used herein, a subject is "need" or "required" of such treatment if the subject will benefit from it biologically, medically, or in terms of quality of life.

[0066] As used herein, unless otherwise indicated herein or clearly contradicted by the context, the terms “a / an”, “the”, and similar terms used in the context of this invention (particularly in the context of the claims) shall be interpreted to cover both the singular and the plural.

[0067] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. The use of any and all instances or exemplary language (e.g., "as") provided herein is intended only to better illustrate the invention and not to limit the scope of the otherwise claimed invention.

[0068] As used herein, the term “inhibit (inhibition or inhibiting)” means the reduction or suppression of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0069] As used herein, the term "treat, treating, or treatment" for any disease or disorder, in one embodiment, means improving the disease or disorder (i.e., slowing down or halting or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat, treating, or treatment" means improving or alleviating at least one bodily parameter, including those that cannot be discerned by the patient. In yet another embodiment, "treat, treating, or treatment" means regulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of bodily parameters), or both. In one embodiment, "treat or treating" means delaying the progression of the disease or disorder.

[0070] As used herein, the term “prevent, preventing, or prevention” for any disease or disorder refers to preventive treatment of the disease or disorder; or delaying the onset of the disease or disorder.

[0071] The term “comprising” encompasses both “including” and “consisting of”; for example, a composition comprising X may consist of only X, or may include additional components, such as X and Y.

[0072] As used herein, the term "combination" refers to a fixed combination, or combination administration, of a dosage unit, in which the crystal form of a compound having formula (I) and its combination partner (i.e., an immunotherapeutic agent) can be administered independently at the same time or separately at time intervals, particularly where these time intervals allow the combination partner to exhibit synergy, such as a co-existing effect. Individual components may be packaged in a single box or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration.

[0073] As used herein, the terms “co-administration” or “combination administration” mean to cover the administration of a selected combination of drugs to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the drugs are not necessarily administered via the same route of administration or administered simultaneously.

[0074] As used herein, the terms "drug combination" and "combination product" are used interchangeably and refer to a fixed combination or a non-fixed combination or kit for combined administration in the form of a single dose unit, wherein two or more therapeutic agents may be administered independently at the same time or separately at time intervals, particularly where these time intervals allow the combination couple to exhibit synergistic effects, such as a co-existing effect. The term "fixed combination" means the crystalline form of a compound having formula (I) and the combination couple (i.e., an immunotherapeutic agent), administered simultaneously to a patient as a single entity or dose. The term "non-fixed combination" means the crystalline form of a compound having formula (I) and the combination couple (i.e., an immunotherapeutic agent), administered simultaneously, in parallel, or sequentially to a patient as separate entities (without a specific time limit), wherein such administration provides a therapeutically effective level of the two compounds in the patient's body. The latter also applies to cocktail therapies, such as the administration of three or more therapeutic agents. In a preferred embodiment, the drug combination is a non-fixed combination.

[0075] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat BTK-related diseases as described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as administration in a single capsule containing the active ingredients in a fixed ratio. Alternatively, such administration encompasses co-administration in multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration also encompasses the sequential use of each type of therapeutic agent at substantially the same time or at different times. In any case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the condition or disorder described herein.

[0076] Crystal form: This disclosure involves N- (3-(6-amino-5-(2-( N- The amorphous form of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (a compound having formula (I)) is described and characterized herein.

[0077] In one embodiment, this disclosure provides N- (3-(6-amino-5-(2-( N-The crystalline form (Type A) of methacrylamido(ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide has an X-ray powder diffraction (XRPD) pattern containing a representative peak at 23.9 ± 0.2 °2θ, measured at a temperature of about 25°C. In another embodiment, the XRPD pattern further includes one or more additional representative peaks selected from 15.6 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, and 23.4 ± 0.2 °2θ. In one aspect of the foregoing embodiment, the XRPD pattern further includes 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 one aspect of the foregoing embodiments, the XRPD plot of crystal form A of the compound having formula (I) may further include measurements taken at a temperature of about 25°C, selecting one, two, three, or four representative peaks selected from 9.2 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 25.2 ± 0.2 °2θ, and 29.6 ± 0.2 °2θ. Therefore, the XRPD diagram of crystal form A of the compound having formula (I) can be measured at a temperature of about 25 °C, selected from 7.8 ± 0.2 °2θ, 9.2 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 13.6 ± 0.2 °2θ, 15.6 ± 0.2 °2θ, 16.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 22.1 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, 23.9 ± 0.2 °2θ, 24.8 ± 0.2 °2θ, 25.2 ± 0.2 °2θ, 25.5 ± 0.2 °2θ. One or more representative peaks of °2θ, 27.2 ± 0.2 °2θ, and 29.6 ± 0.2 °2θ. The XRPD plot of crystal form A may contain one or more (e.g., two, three, four, five, or six) representative peaks selected from those disclosed in Table 1 and measured at a temperature of about 25 °C.

[0078] In another aspect of the above embodiments, the crystal form A of the compound having formula (I) is characterized by the following X-ray powder diffraction pattern, which comprises four or more 2θ values ​​(CuKα λ = 1.54184 Å) selected from the group consisting of: 7.8 ± 0.2 °2θ, 9.2 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 13.6 ± 0.2 °2θ, 15.6 ± 0.2 °2θ, 16.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 22.1 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, 23.9 ± 0.2 °2θ, 24.8 ± 0.2 °2θ, 25.2 ± 0.2 °2θ, 25.5 ± 0.2 °2θ, 27.2 ± 0.2 °2θ, and 29.6 ± 0.2 °2θ. In another aspect of the above embodiments, the crystal form A of the compound having formula (I) is characterized by the following X-ray powder diffraction pattern, which comprises five or more 2θ values ​​(CuKα λ = 1.54184 Å) selected from the group consisting of: 7.8 ± 0.2 °2θ, 9.2 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 13.6 ± 0.2 °2θ, 15.6 ± 0.2 °2θ, 16.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 22.1 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, 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.

[0079] In yet another aspect of the above embodiments, the crystal form A of the compound having formula (I) has substantially the following properties: Figure 1 The XRPD diagram shown.

[0080] N- (3-(6-amino-5-(2-( N-Crystal form A of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide can be thermally characterized. In one embodiment, crystal form A of the compound having formula (I) has the following thermal profile, measured by differential scanning calorimetry (DSC) at a heating rate of 10 °C / min, which includes a single endothermic peak starting at approximately 194 °C (corresponding to melting).

[0081] In another embodiment, the crystal form A of the compound having formula (I) has substantially as follows Figure 2 The DSC thermal analysis diagram shown is illustrated. It should be understood that the hydration form depends on the instrument parameters and can produce different thermal analysis diagrams (in terms of peak shape and profile). Therefore, when data are generated on two different instruments, the same material can have thermal analysis diagrams that look substantially different from each other.

[0082] In another embodiment, the crystal form A of the compound having formula (I) has the same Figure 3 The thermogravimetric analysis (TGA) plots shown are essentially the same. The TGA weight loss is approximately 0.3% in the temperature range of 40°C–200°C. Thermal decomposition occurs at 240°C.

[0083] In yet another embodiment, crystal form A is substantially pure.

[0084] In yet another embodiment, crystal form A is substantially chemically pure.

[0085] In yet another embodiment, crystal form A is substantially phase-pure.

[0086] In one embodiment, the present invention relates to the preparation of compounds N- (3-(6-amino-5-(2-( N- A method for obtaining crystal form A of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: a) will N -(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and acrylic anhydride are reacted in a non-chlorinated solvent, optionally in the presence of an inorganic base; and b) Separate the solid crystal form A (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

[0087] In another embodiment, the present invention relates to the preparation of compounds N- (3-(6-amino-5-(2-( N-A method for obtaining crystal form A of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: (a) will N -(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and acrylic anhydride are reacted in a non-chlorinated solvent, optionally in the presence of a base; (b) Add water to quench the reaction to form an aqueous phase and an organic phase; (c) Separation of the organic phase; (d) Wash the organic phase with an acid solution; and (e) Separate the solid crystal form A (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

[0088] In one aspect of the two aforementioned embodiments, step (a) of the method is performed at a temperature of about 20°C to about 65°C. Preferably, step (a) is performed at a temperature of about 40°C to about 65°C, and most preferably, at a temperature of about 50°C.

[0089] In another aspect of the three embodiments described above, step (a) of the method is carried out in a nonchlorinated solvent selected from ethyl acetate and isopropyl acetate, preferably ethyl acetate.

[0090] In another aspect of the aforementioned four embodiments, step (a) is carried out in the presence of an inorganic base, preferably a carbonate base, and more preferably sodium carbonate.

[0091] In another aspect of the foregoing five embodiments, the method further includes a step following step (b) but preceding step (c), the step comprising: stirring and heating the reaction mixture to a temperature of approximately 50°C to approximately 65°C, and cooling it to room temperature prior to step (c). This additional step can be used to more effectively remove acrylic acid byproducts.

[0092] In another aspect of the six embodiments described above, the acid solution used in step (d) has a pH of about 1. For example, the acid solution is a sulfuric acid solution (e.g., 0.05 M). The organic phase is washed with the acid solution to remove the following byproducts from the reaction mixture: .

[0093] In another aspect of the foregoing seven embodiments, type A is separated into a solid by antisolvent crystallization. The antisolvent is a solvent in which the compound having formula (I) has low solubility (e.g., less than 0.5 mg / mL, preferably less than 0.25 mg / mL). Non-limiting examples of antisolvents used in the method are heptane, hexane, tert-butyl methyl ether, toluene, or acetonitrile.

[0094] In another preferred aspect of the aforementioned seven embodiments, type A is separated into solids by a distillation process.

[0095] The present invention also provides a method for preparing N- (3-(6-amino-5-(2-( N- A type A method for (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: (a) will N- (3-(6-amino-5-(2-( N- The crystal form of methacrylamido(ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is B or N- (3-(6-amino-5-(2-( N- Crystal forms C, or mixtures of B and C forms of methacrylamidoyl(ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, suspended in a non-chlorinated solvent; and (b) and separated into solid form A (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

[0096] The present invention also provides a method for preparing N- (3-(6-amino-5-(2-( N- A type A method for (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: (a) will N- (3-(6-amino-5-(2-( N- The crystal form of methacrylamido(ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is B or N- (3-(6-amino-5-(2-( N- Crystal forms C, or mixtures of B and C forms of methacrylamidoyl(ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, suspended in a non-chlorinated solvent; and (b) Allow the suspension to equilibrate at room temperature for at least 2 weeks, or allow it to equilibrate at 50°C for at least 1 week; and (c) Separation of type A as a solid (e.g., by antisolvent crystallization, cooling crystallization, distillation process or evaporation of solvent).

[0097] In one aspect of the two aforementioned embodiments, the non-chlorinated solvent is selected from 1,4-dioxane, alcohol, acetone, acetonitrile, tetrahydrofuran, water, pyridine, nitromethane, anisole, and alkyl acetate.

[0098] In yet another aspect of the three embodiments described above, depending on the non-chlorinated solvent, crystalline form B or crystalline form C, or mixtures thereof, can be dissolved. In this case, separation of form A as a solid may involve antisolvent crystallization, cooling crystallization, distillation, or solvent evaporation. In other aspects, forms B, C, or mixtures thereof may remain in suspension, in which case form A is separated by filtration.

[0099] The present invention further provides N- (3-(6-amino-5-(2-( N- The crystalline form (type B) of methacrylamido(ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide has an X-ray powder diffraction (XRPD) pattern comprising a representative peak at 20.9 ± 0.2 °2θ, measured at a temperature of about 25 °C. In another embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 6.7 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 17.9 ± 0.2 °2θ, 20.2 ± 0.2 °2θ, 20.9 ± 0.2 °2θ, and 24.0 ± 0.2 °2θ, measured at a temperature of about 25 °C. In one aspect of the foregoing embodiments, the XRPD plot of crystal form B may further include measurements taken at a temperature of about 25°C, selecting one, two, three, or four representative peaks from 5.9 ± 0.2 °2θ, 13.0 ± 0.2 °2θ, 14.8 ± 0.2 °2θ, 19.0 ± 0.2 °2θ, and 22.6 ± 0.2 °2θ.

[0100] Therefore, the XRPD pattern of Form B can contain a pattern selected from 5.9 ± 0.2 °2θ, 6.7 ± 0.2 °2θ, 7.8 ± 0.2 °2θ, 8.3 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 12.1 ± 0.2 °2θ, 12.6± 0.2 °2θ, 13.0 ± 0.2 °2θ, 13.3 ± 0.2 °2θ, 14.8 ± 0.2 °2θ, 15.8 ± 0.2 °2θ, 16.4 ± 0.2 °2θ, 17.6± 0.2 °2θ, 19.5± 0.2 °2θ, 20.2 ± 0.2 °2θ, 20.6 ± 0.2 °2θ, 20.9 ± 0.2 °2θ, 21.6 ± 0.2 °2θ, 22.3 ± The XRPD plot of crystal form B may include one or more (e.g., two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 2, as well as one or more (e.g., two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 2, measured at a temperature of approximately 25°C.

[0101] In another embodiment, the type B is characterized by the following X-ray powder diffraction pattern, which comprises four or more 2θ values ​​(CuKα λ = 1.54184 Å) measured at a temperature of approximately 25 °C, selected from the group consisting of: 5.9 ± 0.2 °2θ, 6.7 ± 0.2 °2θ, 7.8 ± 0.2 °2θ, 8.3 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 12.1 ± 0.2 °2θ, 12.6 ± 0.2 °2θ, 13.0 ± 0.2 °2θ, 13.3 ± 0.2 °2θ, 14.8 ± 0.2 °2θ, 15.8 ± 0.2 °2θ, 16.4 ± 0.2 °2θ, 17.6 ± 0.2 °2θ, 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.

[0102] In another embodiment, the type B is characterized by the following X-ray powder diffraction pattern, comprising five or more 2θ values ​​(CuKα λ = 1.54184 Å) measured at approximately 25 °C, selected from the group consisting of: 5.9 ± 0.2 °2θ, 6.7 ± 0.2 °2θ, 7.8 ± 0.2 °2θ, 8.3 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 12.1 ± 0.2 °2θ, 12.6 ± 0.2 °2θ, 13.0 ± 0.2 °2θ, 13.3 ± 0.2 °2θ, 14.8 ± 0.2 °2θ, 15.8 ± 0.2 °2θ, 16.4 ± 0.2 °2θ, 17.6 ± 0.2 °2θ, 19.5 ± 0.2 °2θ, 20.2 °2θ. ±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.

[0103] In yet another embodiment, the crystal form B of the compound having formula (I) has essentially the following properties: Figure 4 The XRPD diagram shown.

[0104] N- (3-(6-amino-5-(2-( N- The crystal form B of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide can be thermally characterized. In one embodiment, the crystal form B of the compound having formula (I) has a differential thermogravimetric curve measured by DSC at a heating rate of 10 °C / min, which includes an endothermic peak starting at about 170 °C (corresponding to the melting of variant B), an exothermic peak starting at about 175 °C (corresponding to recrystallization to variant A), and an endothermic peak starting at about 194 °C (corresponding to the melting of variant A).

[0105] In another embodiment, the crystal form B of the compound having formula (I) has essentially the following properties: Figure 5 The DSC thermal analysis diagram shown is illustrated. It should be understood that the hydration form depends on the instrument parameters and can produce different thermal analysis diagrams (in terms of peak shape and profile). Therefore, when data are generated on two different instruments, the same material can have thermal analysis diagrams that look substantially different from each other.

[0106] In another embodiment, the crystal form B of the compound having formula (I) has the same... Figure 6The thermogravimetric analysis (TGA) plots shown are essentially the same. The TGA weight loss is approximately 0.2% in the range of 40°C–160°C. Thermal decomposition occurs above 240°C.

[0107] In yet another embodiment, crystal form B is substantially pure.

[0108] In yet another embodiment, crystal form B is substantially chemically pure.

[0109] In yet another embodiment, crystal form B is substantially phase-pure.

[0110] In one embodiment, the present invention relates to the preparation of compounds N- (3-(6-amino-5-(2-( N- A method for obtaining crystal form B of methacrylamide (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: (a) Suspension of type A in dichloromethane for approximately 3 days at a temperature of approximately 40°C; (b) Allow the suspension to equilibrate at room temperature for approximately 5 days; and (c) Separate the B type as a solid (e.g., by filtration).

[0111] In yet another embodiment, the present invention relates to the preparation of compounds. N- (3-(6-amino-5-(2-( N- A method for obtaining crystal form B of methacrylamide (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: a) Suspend variant A in a solvent mixture containing at least 50% dichloromethane by volume; b) Allow the suspension to equilibrate at approximately 50°C for about 2 weeks; c) Cool the suspension to room temperature; and d) Separating solids from a suspension (e.g., by filtration).

[0112] In one aspect of the above embodiments, the solvent mixture is MeOH / dichloromethane 50:50 (v / v).

[0113] The present invention further provides N- (3-(6-amino-5-(2-( N-The crystalline form (type C) of methacrylamido(ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide has an X-ray powder diffraction (XRPD) pattern comprising a representative peak at 5.9 ± 0.2 °2θ, measured at a temperature of about 25 °C. In another embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 11.9 ± 0.2 °2θ, 17.0 ± 0.2 °2θ, and 19.3 ± 0.2 °2θ, measured at a temperature of about 25 °C. In one aspect of the foregoing embodiments, the XRPD plot of crystal form C may further include measurements taken at a temperature of about 25°C, selecting one, two, three, or four representative peaks from 12.5 ± 0.2°2θ, 15.3 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.2 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, and 23.7 ± 0.2 °2θ.

[0114] Therefore, the XRPD diagram of crystal form C can include values ​​selected from 5.9 ± 0.2 °2θ, 11.9 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 12.5 ± 0.2 °2θ, 12.9 ± 0.2 °2θ, 14.4 ± 0.2 °2θ, 14.6 ± 0.2 °2θ, 15.3 ± 0.2 °2θ, 17.0 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 19.0 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 20.2 ± 0.2 °2θ, 20.8 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.2 ± 0.2 °2θ, and 22.8 ± 0.2 °2θ. The XRPD plot of crystal form C may include one or more (e.g., two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 3, as well as one or more (e.g., two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 3, measured at a temperature of approximately 25°C.

[0115] In another embodiment, the C-type is characterized by an X-ray powder diffraction pattern comprising four or more 2θ values ​​(CuKα λ = 1.54184 Å) selected from the group consisting of: 5.9 ± 0.2 °2θ, 11.9 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 12.5 ± 0.2 °2θ, 12.9 ± 0.2 °2θ, 14.4 ± 0.2 °2θ, 14.6 ± 0.2 °2θ, 15.3 ± 0.2 °2θ, 17.0 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 19.0 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 20.2 ± 0.2 °2θ. °2θ, 20.8± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.2 ± 0.2 °2θ, 22.8 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, 23.7± 0.2 °2θ, 25.3 ± 0.2 °2θ, 26.1 ± 0.2 °2θ, and 26.9 ± 0.2 °2θ.

[0116] In another embodiment, the C-type is characterized by the following X-ray powder diffraction pattern, comprising five or more 2θ values ​​(CuKα λ = 1.54184 Å) measured at approximately 25 °C, selected from the group consisting of: 5.9 ± 0.2 °2θ, 11.9 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 12.5 ± 0.2 °2θ, 12.9 ± 0.2 °2θ, 14.4 ± 0.2 °2θ, 14.6 ± 0.2 °2θ, 15.3 ± 0.2 °2θ, 17.0 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 19.0 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 20.2 ± 0.2 °2θ. °2θ, 20.8± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.2 ± 0.2 °2θ, 22.8 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, 23.7± 0.2 °2θ, 25.3± 0.2 °2θ, 26.1 ± 0.2 °2θ, and 26.9 ± 0.2 °2θ.

[0117] In yet another embodiment, the crystal form C of the compound having formula (I) has substantially the following properties: Figure 7 The XRPD diagram shown.

[0118] N-(3-(6-amino-5-(2-( N- The crystal form C of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide can be thermally characterized. In one embodiment, the crystal form C of the compound having formula (I) has a differential thermogravimetric curve measured by DSC at a heating rate of 10 °C / min, which includes a small exothermic peak between 90 °C and 120 °C (corresponding to the solid / solid transition from variant C to variant B), an endothermic peak starting at about 171 °C (corresponding to the melting of variant B), an exothermic peak starting at about 175 °C (corresponding to recrystallization to variant A), and an endothermic peak starting at about 195 °C (corresponding to the melting of variant A).

[0119] In another embodiment, the crystal form C of the compound having formula (I) has substantially the following properties: Figure 8 The DSC thermal analysis diagram shown is illustrated. It should be understood that the hydration form depends on the instrument parameters and can produce different thermal analysis diagrams (in terms of peak shape and profile). Therefore, when data are generated on two different instruments, the same material can have thermal analysis diagrams that look substantially different from each other.

[0120] In another embodiment, crystal form C has the same properties as... Figure 9 The thermogravimetric analysis (TGA) plots shown are essentially the same. The TGA weight loss is approximately 0.01% in the temperature range of 40°C–150°C. Thermal decomposition occurs above 240°C.

[0121] In yet another embodiment, crystal form C is substantially pure.

[0122] In yet another embodiment, crystal form C is chemically phase-pure.

[0123] In yet another embodiment, crystal form C is substantially phase-pure.

[0124] In one embodiment, the present invention relates to the preparation of compounds N- (3-(6-amino-5-(2-( N- A method for determining crystal form C of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: a) Progenitor A was suspended in dichloromethane at a temperature of approximately 40°C for about 3 days; b) Cool the suspension to room temperature; c) Separate C-type solids (e.g., by filtration).

[0125] In another embodiment, the present invention relates to the preparation of compounds N- (3-(6-amino-5-(2-(N- A method for determining crystal form C of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: a) Suspend variant A in a solvent mixture containing at least 50% dichloromethane; b) Allow the suspension to equilibrate at room temperature for approximately 4 weeks; c) Separate C-type solids (e.g., by filtration).

[0126] In one aspect of the above embodiments, the solvent mixture is MeOH / dichloromethane 50:50 (v / v).

[0127] In another embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount N- (3-(6-amino-5-(2-( N- The invention relates to a crystalline form (type A, type B, or combination thereof) of methacrylamide (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In a specific embodiment, the invention relates to a pharmaceutical composition comprising crystalline form A and one or more pharmaceutically acceptable carriers, diluents, or excipients. In yet another aspect, the invention relates to a pharmaceutical composition comprising crystalline form A in a substantially pure form. In yet another aspect, the invention relates to a pharmaceutical composition comprising crystalline form B in a substantially pure form. In yet another embodiment, the invention relates to a pharmaceutical formulation comprising crystalline form A and further comprising at least one other solid form. N- (3-(6-amino-5-(2-( N- Methacrylamide (methacrylamido)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. N- (3-(6-amino-5-(2-( N- Methacrylamide (ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, In other embodiments, the present invention relates to combinations, specifically drug combinations, the combinations comprising a therapeutically effective amount N- (3-(6-amino-5-(2-( N- The crystal forms (A, B or combinations thereof) of methacrylamido(ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, and one or more therapeutic agents.

[0128] In a specific embodiment, the present invention relates to a pharmaceutical combination comprising crystal form A and one or more therapeutic agents. In yet another aspect, the present invention relates to a pharmaceutical combination comprising crystal form A in a substantially pure form and one or more therapeutic agents. In yet another aspect, the present invention relates to a pharmaceutical combination comprising crystal form B in a substantially pure form and one or more therapeutic agents. In yet another embodiment, the present invention relates to a pharmaceutical combination comprising crystal form A and further comprising at least one other solid form. N- (3-(6-amino-5-(2-( N- Methacrylamide (methacrylamido)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. N- (3-(6-amino-5-(2-( N- Methacrylamide (ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

[0129] In another embodiment, the present invention provides a pharmaceutical combination as described herein, wherein the therapeutic agent is independently selected from the group consisting of: immunosuppressants or immunomodulators or other anti-inflammatory agents (e.g. for the treatment or prevention of acute or chronic rejection or inflammation and autoimmune disorders of allogeneic grafts or xenografts) or chemotherapeutic agents (e.g., antiproliferative agents of malignant cells). For example, the crystal form of a compound having formula (I) can be used in combination with: calcineurin inhibitors, such as cyclosporine A or FK 506; mTOR inhibitors, such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA-93, biolimus-7, or basiloxane-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; imidazolidinedin; mycophenolic acid or its salt; mycophenolate mofetil; 15-deoxyguanidin or its immunosuppressive homologues, analogues, or derivatives; PKC inhibitors, such as those disclosed in WO 02 / 38561 or WO In 03 / 82859, for example, compounds of examples 56 or 70; JAK3 kinase inhibitors, such as N-benzyl-3,4-dihydroxy-benzylidene-cyanoacetamide □-cyano-(3,4-dihydroxy)-]N-benzylcinnamamide (tyrosine phosphorylation inhibitor AG) 490), styraxin 25-C (PNU156804), [4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P131), [4-(3'-bromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P154), [4-(3',5'-dibromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] WHI-P97, KRX-211, 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile, in free form or in pharmaceutically acceptable salt form, such as monocitrate (also known as CP-690,550), or as disclosed in WO Compounds disclosed in WO 04 / 052359 or WO 05 / 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, such as MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or ligands thereof;Other immunomodulatory compounds, such as recombinant binding molecules having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, such as at least the extracellular portion of CTLA4 that binds to a non-CTLA4 protein sequence, such as CTLA4Ig (e.g., designated ATCC68629) or a mutant thereof, or a mutant thereof, such as LEA29Y; adhesion molecule inhibitors, such as LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists, or VLA-4 antagonists; or chemotherapeutic agents, such as paclitaxel, gemcitabine, cisplatin, doxorubicin, or 5-fluorouracil; or anti-infective agents. Further co-occurring conjugates of compounds having formula (I) may be selected from: PI3K inhibitors (e.g., pan- or α, β, γ, δ-selective), TNF inhibitors, IL1β inhibitors, IL17 inhibitors, and inhibitors of IL6 or IL receptors.

[0130] In one embodiment, the present invention relates to a method for treating a disease or disorder typically improved by inhibiting BTK in a subject of need, the method comprising: administering, alone or in combination with one or more therapeutic agents, a therapeutically effective amount of... N- (3-(6-amino-5-(2-( N- Crystal forms of (A, B or a combination thereof, preferably A) of methacrylamidoyl(ethoxy)pyrimidin-4-yl(5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

[0131] In another embodiment, the present invention relates to a method for treating diseases or disorders (such as inflammation and autoimmune disorders and lung and respiratory tract inflammation) that are typically improved by inhibiting BTK in a subject in need, the method comprising administering, alone or in combination with one or more therapeutic agents, the pharmaceutical composition described herein to the subject.

[0132] In another embodiment, the present invention relates to a method for treating diseases or disorders (such as inflammation and autoimmune disorders and lung and respiratory tract inflammation) that are typically improved by inhibiting BTK in a subject in need, the method comprising administering to the subject a combination of drugs as described herein.

[0133] In one embodiment, the present invention relates to N- (3-(6-amino-5-(2-( N- Use of crystalline forms (type A, type B, or combinations thereof, or preferably type A) of methacrylamide (methacrylamide-ethoxypyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, alone or in combination with one or more therapeutic agents, for the treatment of diseases or disorders (e.g., inflammation and autoimmune disorders, as well as inflammation of the lungs and respiratory tract) that are typically improved by inhibiting BTK.

[0134] In yet another embodiment, the present invention relates to... N- (3-(6-amino-5-(2-( N- Crystal forms of (A, B, or a combination thereof, or preferably A) of methacrylamide (methacrylamidoyl)ethoxypyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide are intended for use in the treatment of diseases or disorders typically improved by BTK inhibition, such as inflammation and autoimmune disorders as well as inflammation of the lungs and respiratory tract.

[0135] In yet another embodiment, the present invention relates to... N- (3-(6-amino-5-(2-( N- A combination of a crystalline form (A, B, or a combination thereof, or preferably A) of methacrylamide (methacrylamidoyl)ethoxypyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and one or more therapeutic agents for use in the treatment of diseases or disorders typically improved by inhibiting BTK.

[0136] In one embodiment, the present invention relates to methods of treatment, uses, compounds for use, or combinations for use as described herein, wherein diseases or disorders typically improved by inhibiting BTK are selected from inflammatory and autoimmune disorders as well as lung and respiratory tract inflammation. More specifically, diseases or disorders typically improved by BTK inhibition are selected from autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and transplant rejection; diseases in which antibody production, antigen presentation, cytokine production, or lymphoid organogenesis are abnormal or undesirable; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic spontaneous urticaria, induced urticaria), and chronic allergies (atopic dermatitis, irritative urticaria, etc.). Contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpassch syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism; hematopoietic cancers, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenstrom's disease. Preferably, the diseases or disorders that are typically improved by inhibiting BTK are selected from rheumatoid arthritis; chronic urticaria, preferably chronic spontaneous urticaria; Sjögren's syndrome, multiple sclerosis, or asthma.

[0137] It has been found that crystal form A, as described in this paper, has advantageous properties.

[0138] The A form of the compound having formula (I) is the most stable form. The A form is physically stable when exposed to high levels of % RH and under prolonged stress conditions. The A form is also stable in suspension in non-chlorinated solvents, such as those other than dichloromethane and chloroform.

[0139] If it is type A of the present invention, due to its non-hygroscopic nature, it retains its physicochemical properties regardless of the relative humidity of the surrounding atmosphere. This facilitates easier and more reliable manufacturing methods and easier storage of pharmaceutical products containing type A. Furthermore, crystal form A retains its crystal structure even when subjected to harsh temperature and / or humidity stress conditions, or when subjected to prolonged pulping in various solvents.

[0140] It was found that chloroform and dichloromethane solvents led to the formation of variant B and / or variant C.

[0141] Variant C is a metastable form because it transforms into variant B at room temperature or by heating at 50°C.

[0142] Variant B is stable at temperatures up to 170°C, but it transforms into variant A above 170°C.

[0143] Drug composition, dosage and administration In one embodiment, the present document describes N- (3-(6-amino-5-(2-( N- The crystalline forms of methacrylamide (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide can be used alone or formulated into pharmaceutical compositions, said pharmaceutical compositions further comprising at least one pharmaceutically acceptable excipient, and typically comprising at least two or more pharmaceutically acceptable excipients. Some suitable excipients are disclosed herein. Other excipients known in the art may be used without departing from the purpose and scope of this application.

[0144] In some embodiments, the present invention utilizes a pharmaceutical composition comprising the compounds of the present invention and pharmaceutically acceptable excipients.

[0145] As used herein, the term "pharmaceuticalally acceptable excipient" includes any and all solvents, carriers, diluents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal, antioxidant), isotonic agents, absorption delay agents, salts, pharmaceutical stabilizers, binders, additives, swelling agents, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). It should be understood that the use of any conventional excipient in any therapeutic or pharmaceutical composition is contemplated unless the conventional excipient is incompatible with the active ingredient.

[0146] The pharmaceutical compositions can be formulated for specific routes of administration, such as oral, parenteral, and rectal administration. Furthermore, the pharmaceutical compositions of the present invention can be in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). The pharmaceutical compositions can undergo routine pharmaceutical processes (such as sterilization) and / or may contain conventional inert diluents, lubricants, carriers or buffers, and excipients (such as solvents, preservatives, stabilizers, wetting agents, emulsifiers, and swelling agents).

[0147] Typically, the pharmaceutical composition is a tablet or capsule comprising an active ingredient together with at least one excipient, such as: a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; in the case of tablets, also comprising... c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; if desired; d) Carriers, such as aqueous media containing co-solventizing materials, such as captisol, PEG, glycerol, cyclodextrin, etc.; e) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and / or f) Adsorbents, colorants, flavoring agents, and sweeteners.

[0148] Tablets can be film-coated or enteric-coated using methods known in the art.

[0149] Preferably, the compound or composition is prepared for oral administration, such as tablets or capsules, and optionally packaged in a multi-dose form suitable for storage and / or dispensing unit doses of the pharmaceutical product. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0150] Tablets may contain an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets are either uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0151] The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can promote the degradation of certain compounds.

[0152] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-aqueous components and under low moisture or low humidity conditions. The anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, it is preferable to use materials known to prevent exposure to water to package the anhydrous compositions so that they can be included in suitable dispensing containers. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0153] The present invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate of decomposition of the compounds of the present invention as active ingredients. Such agents (referred to herein as "stabilizers") include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers.

[0154] For subjects weighing approximately 50-70 kg, the pharmaceutical compositions or combinations of the present invention may be in the form of one or more active ingredients at a unit dose of approximately 1-1000 mg, or approximately 1-500 mg, or approximately 1-250 mg, or approximately 1-150 mg, or approximately 0.5-100 mg, or approximately 10-50 mg of active ingredient. Preferably, the pharmaceutical compositions or combinations of the present invention may be in the form of a unit dose of approximately 10 mg, approximately 25 mg, or approximately 50 mg. The therapeutically effective dose or amount of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition, disorder, or disease being treated, or its severity. A physician, clinician, or veterinarian with ordinary skills can readily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of the disorder or disease.

[0155] The above-described dosage characteristics are demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and products. The compounds of the present invention can be applied in vitro in solution form (e.g., preferably an aqueous solution), and in vivo, such as in the enteral, parenteral, or preferably intravenous, suspension, or in an aqueous solution. In vitro doses can be approximately 10... -3 molar concentration and 10 -9 The effective therapeutic dose can be within the range of molar concentrations. Depending on the route of administration, the effective therapeutic dose in vivo can be between about 0.1-500 mg / kg, or between about 1-100 mg / kg. Preferably, the effective therapeutic dose in vivo is between about 10 mg and about 200 mg daily, for example, in the range of about 10 mg, about 20 mg, about 25 mg, about 35 mg, about 50 mg, about 100 mg, or about 200 mg daily. Preferably, the effective therapeutic dose in vivo is selected from about 10 mg, about 35 mg, about 50 mg, or about 100 mg once daily. More preferably, the effective therapeutic dose in vivo is selected from about 10 mg, about 25 mg, about 50 mg, or about 100 mg twice daily.

[0156] In other embodiments, a pharmaceutical composition is provided comprising at least one crystal form (e.g., type A, type B, or a mixture thereof, preferably type A) as described in the embodiments above herein; and at least one pharmaceutically acceptable carrier.

[0157] Therefore, in the embodiments disclosed herein, N- (3-(6-amino-5-(2-( N- The crystalline form (type A or type B, preferably type A) of methacrylamido(ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is provided in substantially phase-pure form. This substantially phase-pure form... N-(3-(6-amino-5-(2-( N- The crystal form (type A or type B) of methacrylamido(ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide can be used to prepare pharmaceutical compositions, which may further comprise one or more pharmaceutically acceptable excipients.

[0158] combination: The crystalline forms of the compounds of formula (I) of the present invention (e.g., type A or type B, or mixtures thereof, preferably type A) can be administered simultaneously with or before or after one or more therapeutic agents. The crystalline forms of the present invention can be administered separately via the same or different routes of administration as other pharmaceutical agents, or together in the same pharmaceutical composition.

[0159] The crystal form of a compound having formula (I) can be administered as a single active ingredient or in combination with other drugs (e.g., immunosuppressants or immunomodulators) or other anti-inflammatory agents (e.g., for the treatment or prevention of acute or chronic rejection or inflammation and autoimmune disorders of allogeneic or xenografts) or chemotherapeutic agents (e.g., antiproliferative agents of malignant cells) as adjuvants. For example, compounds having formula (I) can be used in combination with: calcineurin inhibitors, such as cyclosporine A or FK 506; mTOR inhibitors, such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA-93, biolimus-7, or basiloxane-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; imidazolidinedin; mycophenolic acid or its salt; mycophenolate mofetil; 15-deoxyguanidin or its immunosuppressive homologues, analogues, or derivatives; PKC inhibitors, such as those disclosed in WO 02 / 38561 or WO In 03 / 82859, for example, compounds of examples 56 or 70; JAK3 kinase inhibitors, such as N-benzyl-3,4-dihydroxy-benzylidene-cyanoacetamide α-cyano-(3,4-dihydroxy)-]N-benzylcinnamamide (tyrosine phosphorylation inhibitor AG 490), styracin 25-C (PNU156804), [4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P131), [4-(3'-bromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P154), [4-(3',5'-dibromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] [Pholine] WHI-P97, 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 pharmaceutically acceptable salt form, such as monocitrate (also known as CP-690,550), or as disclosed in WO04 / 052359 or WO Compounds disclosed in 05 / 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, such as MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or ligands thereof;Other immunomodulatory compounds, such as recombinant binding molecules having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, such as at least the extracellular portion of CTLA4 that binds to a non-CTLA4 protein sequence, such as CTLA4Ig (e.g., designated ATCC 68629) or a mutant thereof, or a mutant thereof, such as LEA29Y; adhesion molecule inhibitors, such as LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists, or VLA-4 antagonists; or chemotherapeutic agents, such as paclitaxel, gemcitabine, cisplatin, doxorubicin, or 5-fluorouracil; or anti-infective agents. Further co-occurring conjugates of compounds having formula (I) may be selected from: PI3K inhibitors (e.g., pan- or α, β, γ, δ-selective), TNF inhibitors, IL1β inhibitors, IL17 inhibitors, and inhibitors of IL6 or IL receptors.

[0160] Treatment box In one embodiment, the invention provides a pillbox containing two or more individual pharmaceutical compositions, at least one of which contains a crystalline form (type A, type B, or a mixture thereof, preferably type A) of a compound having formula (I). In one embodiment, the pillbox includes means for separately retaining the compositions, such as a container, separate bottles, or separate foil packs. An example of such a pillbox is blister packaging, typically used for packaging tablets, capsules, etc.

[0161] The kit of the present invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer separate compositions at different dose intervals, or to titrate separate compositions relative to each other. To aid compliance, the kit of the present invention typically includes instructions for use.

[0162] In the combination therapy of the present invention, the crystalline form of the compound having formula (I) (i.e., type A, type B, or a mixture thereof, preferably type A) and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Moreover, the crystalline form of the compound having formula (I) and other therapeutic agents may be (i) before the combination product is dispensed to a physician (e.g., when the cassette contains the crystalline form of the compound having formula (I) and other therapeutic agents); (ii) by the physician himself (or under the physician's guidance) before administration; and (iii) by the patient himself, for example, during the sequential administration of the crystalline form of the compound having formula (I) and other therapeutic agents into the combination therapy.

[0163] Therefore, the present invention provides the use of the crystal form (i.e., type A, type B, or a mixture thereof, preferably type A) as described herein for treating diseases (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases) that are improved by inhibiting BTK, wherein the preparation of the medicament is for administration in combination with another therapeutic agent. The present invention also provides the use of a therapeutic agent for treating diseases (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases) that are improved by inhibiting BTK, wherein the medicament is administered in combination with a crystal form of a compound having formula (I).

[0164] The present invention also provides crystal forms (i.e., type A, type B, or mixtures thereof, preferably type A) of compounds having formula (I) for use in a method of treating a disease improved by BTK inhibition, wherein the crystal form of the compound having formula (I) is prepared for administration in combination with another therapeutic agent. The present invention also provides another immunotherapeutic agent for use in a method of treating a disease improved by BTK inhibition, wherein other therapeutic agents are prepared for administration in combination with the crystal form of the compound having formula (I). The present invention also provides crystal forms of compounds having formula (I) for use in a method of treating a disease improved by BTK inhibition, wherein the crystal form of the compound having formula (I) is administered in combination with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease improved by BTK inhibition, wherein other therapeutic agents are administered in combination with the crystal form of the compound having formula (I).

[0165] The present invention also provides the use of a crystalline form of a compound having formula (I) for treating diseases (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases) that are improved by inhibiting BTK, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating diseases (e.g., autoimmune diseases, anti-inflammatory diseases, respiratory diseases) that are improved by inhibiting BTK, wherein the patient has previously (e.g., within 24 hours) been treated with a crystalline form of a compound having formula (I).

[0166] N- (3-(6-amino-5-(2-( N- Preparation of the crystal form of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide: Crystal forms can be prepared by a variety of methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid-state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallizing or recrystallizing crystal forms from a solvent or solvent mixture include, for example, evaporating the solvent, lowering the temperature of the solvent or solvent mixture, supersaturating a solvent mixture containing crystal seed molecules and / or salts, freeze-drying a solvent mixture, and adding an antisolvent (extraction solvent) to the solvent mixture. Exemplary methods for preparing the crystal forms described herein are detailed below.

[0167] The crystals of the drug (including polymorphs), preparation methods, and characterization of the drug crystals are disclosed in [the relevant document / document]. Solid-State Chemistry of Drugs [Solid-state chemistry of pharmaceuticals] SR Byrn, RR Pfeiffer, and JGStowell, 2nd ed., SSCI, West Lafayette, Indiana (1999).

[0168] For crystallization techniques using solvents, the choice of one or more solvents typically depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used; for example, the compound can be dissolved in a first solvent to provide a solution, and then an antisolvent can be added to reduce the solubility of the compound in the solution and to facilitate crystal formation. An antisolvent is a solvent in which the compound has low solubility.

[0169] In one method of preparing crystals, the compound is suspended and / or stirred in a suitable solvent to provide a slurry, which may be heated to promote dissolution. As used herein, the term "slurry" refers to a saturated solution of the compound, which may also contain additional amounts of the compound to provide a non-homogeneous mixture of the compound and solvent at a given temperature. This may also be referred to as a suspension.

[0170] Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of specific polymorphs or to control the particle size distribution of the crystalline product. Therefore, the required seed quantity depends on the size of the available seed crystals and the desired size of the average product particles, as illustrated, for example, in "Programmed Cooling of Batch Crystallizers," JW Mullin and J. Nyvlt. Chemical Engineering ScienceAs described in [Chemical Engineering Science], 1971, 26, 369-377. Typically, small-sized seeds are required to effectively control crystal growth in a batch. Small-sized seeds can be generated by sieving, grinding, or micronizing large crystals, or by microcrystallizing the solution. It should be noted that grinding or micronizing crystals does not result in any change in the crystallinity of the crystals forming the desired crystal form (i.e., becoming amorphous or another polymorph).

[0171] The cooled crystallization mixture can be filtered under vacuum, and the separated solids can be washed with a suitable solvent (such as a cold recrystallization solvent) and dried under nitrogen purging to provide the desired crystal form. The separated solids can be analyzed by suitable spectroscopic or analytical techniques, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, etc., to ensure the preferred crystal form of the product. The resulting crystal form is typically produced in an amount greater than about 70% by weight, preferably greater than 90% by weight, based on the weight of the compound initially used in the crystallization process. If desired, the product can be co-ground or passed through a mesh screen to deplete the product.

[0172] Alternatively, the crystal form can be directly derived from the material used for preparation. N- (3-(6-amino-5-(2-( N- The final method of preparing (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide uses a reaction medium. This can be achieved, for example, by using a solvent or mixture of solvents in the final method step, from which crystallization is possible. N- (3-(6-amino-5-(2-( N- Methacrylamide (ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. Furthermore, the crystalline form can be obtained by distillation or solvent addition techniques.

[0173] In addition to the methods briefly discussed below, it should be understood that a variety of analytical methods can be used to characterize any material described herein.

[0174] The following non-limiting examples illustrate this disclosure.

[0175] Example Example 1: Preparation of amorphous type A Will N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Int-10, as disclosed in WO 2015 / 079417) and sodium carbonate were suspended in ethyl acetate and heated to 50°C. A solution of acrylic anhydride in ethyl acetate (20% w / w) was added to the suspension. The reaction mixture was stirred at 50°C for about 30 min. After the addition of water, the reaction mixture was stirred at 65°C for about 30 min. Subsequently, the phases were 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. Then, the organic phase was washed with water and the aqueous phase was removed at 60°C. The final organic phase was treated by low-in-particle filtration. Distillation was carried out under reduced pressure at an internal temperature of 60°C to remove part of the solvent mixture, while ethyl acetate was added to maintain the solvent level approximately constant. This reduced the water content. (Optionally, add a type A seed suspension in ethyl acetate to the solution). Stir the suspension for at least 15 min. Then, further distill under reduced pressure at an internal temperature of 60°C to remove some of the solvent mixture, while adding ethyl acetate to maintain the solvent level approximately constant.

[0176] The suspension was stirred at 60 °C for 30 min, cooled to 30 °C over 200 min, and stirred at 30 °C for 30 min. Final distillation was performed under reduced pressure at an internal temperature of 30 °C, with ethyl acetate added to maintain a roughly constant solvent level. After stirring at 30 °C for 120 min, the suspension was cooled to 0 °C over 300 min and stirred at 0 °C for at least 240 min. The product was separated by centrifugation, and the filter cake was washed twice with ethyl acetate. The separated wet product was dried under vacuum on a tray in a drying oven at 40 °C. Crystal form A was obtained. Variant A was characterized by HR-XRPD, LCMS, TGA, and DSC.

[0177] Example 2: Preparation of amorphous C Variant A (Example 1) was suspended in dichloromethane at 50°C for 3 days. The suspension was then filtered through a Buchner filter. The solids were recovered by filtration and dried overnight under vacuum (200 mbar) at room temperature to obtain variant C. Variant C was stored at -20°C to prevent further conversion.

[0178] Example 3: Preparation of Crystalline Type B Variant C (Example 2) was placed at room temperature and its conversion to variant B was monitored by HR-XRPD, and the conversion was completed after 5 days.

[0179] Variant B and variant C were characterized using HR-XRPD, LCMS, TGA, and DSC.

[0180] Example 4: High-resolution powder X-ray diffraction The solid was finely ground in a mortar with a pestle. An 8 mm borosilicate glass capillary (0.3 mm in diameter) was filled with the compound and carefully placed in a diffractometer.

[0181] HR-XRPD maps were collected at 296 K on a Bruker D8 Advance system equipped with a LynxEye solid-state detector. The radiation used for data collection was monochromated from Cu through a germanium crystal. K α1 (λ = 1.54056 Å). at 4-50° 2 θ Diffraction data for variant A were collected within the range of 3–41.5° 2. θ Diffraction data for variants B and C were collected within the range.

[0182] Table 1: X-ray powder diffraction data of amorphous type A

[0183] Table 2: X-ray powder diffraction data of crystal-agnostic type B

[0184] Table 3: X-ray powder diffraction data of crystalline C

[0185] Example 5: Differential Scanning Calorimetry (DSC) Melting characteristics were obtained from DSC thermal analysis plots and recorded using a heat flux DSC822e instrument (Mettler-Toledo GmbH, Switzerland). The temperature and enthalpy of the DSC822e were calibrated using a small piece of indium (melting point 156.6 °C; ΔH = 28.45 J / g). Samples were sealed in standard 40 μl aluminum disks, either with pinholes or hermetically sealed, and heated in the DSC from -20 °C to 300 °C at heating rates of 2 °C / min, 5 °C / min, 10 °C / min, or 20 °C / min. During measurements, the DSC instrument was purged with dry N2 gas at a flow rate of 50 ml / min.

[0186] Cyclic DSC was performed using the same equipment. The sample was sealed in a standard 40 μl aluminum disk, punctured with a needle, and heated to 195 °C in DSC, cooled to -20 °C, and then heated to 300 °C again. The heating and cooling rates were 10 °C / min.

[0187] The accuracy of sample temperature measured using this method is within approximately ±1°C, and the heat of fusion can be measured within approximately ±5% relative error.

[0188] DSC measurements were performed on variants A, B, and C at different heating rates in open and closed pans, between -20°C and 300°C.

[0189] Figure 2 , Figure 5 and Figure 8 The DSC traces of variants A, B, and C recorded in the open pan are reported separately. The onset temperatures of the exothermic / endothermic events observed in the DSC traces are reported in Tables 4, 5, and 6, respectively.

[0190] In both sets of DSC measurements, an overall shift of thermal events to higher temperatures was observed by increasing the heating rate and expanding the event.

[0191] The DSC curves for variant A show that the initial melting temperatures for both the open and closed discs are in the range of 193-195°C. In the DSC measurements for variant B, the endothermic / exothermic events between 170°C and 180°C may be related to the melting and recrystallization of variant B into A.

[0192] The presence of endothermic / thermal events between 170°C and 180°C in the DSC trace of variant C confirms that variant C is transformed into variant B by heating.

[0193] Table 4: Onset temperatures and enthalpies of endothermic events determined by DSC measurements of variant A in an open pan at heating rates of 2, 5, 10, and 20 °C / min.

[0194] Table 5: Onset temperatures and enthalpies of endothermic and exothermic events determined by DSC measurements of variant B in an open pan at heating rates of 2, 5, 10, and 20 °C / min.

[0195] Table 6: Onset temperatures and enthalpies of endothermic and exothermic events determined by DSC measurements of variant C in an open pan at heating rates of 2, 5, 10, and 20 °C / min.

[0196] Example 6: Thermogravimetric Analysis (TGA): Mass loss due to solvent or water loss in the crystal was determined by TGA / SDTA (single differential calorimetry) and TGMS (thermogravimetric analysis coupled with mass spectrometry). Sample weight was monitored during heating in a TGA / DSC 3+ STARe system (Mettler-Toledo AG, Switzerland), and a weight-to-temperature profile was obtained. Temperature calibration of the TGA / DSC 3+ was performed using indium and aluminum samples. The sample (approximately 2 mg) was weighed into a 100 μL aluminum crucible and sealed. A puncture was made in the seal, and the crucible was heated in the TGA from 25 °C to 300 °C at a heating rate of 10 °C / min. The sample was purged with dry N2 gas. Gas from the TGA sample was analyzed using an Omnistar GSD 301 T2 mass spectrometer (Pfeiffer Vacuum GmbH, Germany). This quadrupole mass spectrometer analyzes mass over a temperature range of 0–200 amu. Temperature was reported in degrees Celsius (°C), and weight loss was reported as a percentage of total mass loss.

[0197] TGA / SDTA analysis of variant A ( Figure 3 The results showed that the mass loss was 0.3% in the temperature range of 40℃-200℃, and the indicator variant A was anhydrous. The endothermic peak around 190℃ in the SDTA curve can be attributed to the melting of the compound. Thermal degradation occurred above 240℃.

[0198] Figure 3 TGA / SDTA analysis of variant A (heating rate 10 °C / min). A 0.3% mass loss was recorded in the range of 40 °C–200 °C. Thermal decomposition occurred above 240 °C.

[0199] TGA / STDA analysis of variant B ( Figure 6 The results show that the mass loss is 0.2% in the temperature range of 40℃–160℃. Therefore, variant B is anhydrous. The events occurring above 160℃ in the SDTA curve are attributed to the melting and recrystallization of variant B into variant A, followed by the final melting of variant A. Thermal degradation occurs above 240℃.

[0200] Figure 6 TGA / SDTA analysis of variant B (heating rate 10 °C / min). A 0.2% mass loss was recorded in the range of 40 °C–160 °C. Thermal decomposition occurred above 240 °C.

[0201] TGMS analysis of variant C ( Figure 9 The results show that the mass loss is 0.01% in the temperature range of 40℃-150℃, and the indicator variant C is an anhydrous crystalline phase. Thermal degradation occurs above 240℃.

[0202] Figure 9TGA / SDTA (20A) and TGMS (20B) analyses of variant C (heating rate 10 °C / min). A mass loss of 0.01% was recorded in the range of 40 °C–150 °C. Thermal decomposition occurred above 240 °C.

[0203] Example 4: Comparison of Physicochemical Stability Variations A, B, and C are subjected to the following stress conditions: • • Store at 80℃ in a sealed vial for 1 month; • • 80℃ / 75% RH in an open vial for 1 month; • • 100℃ in a sealed vial for 3 days; Subsequently, the solids were analyzed by HR-XRPD, TGMS, and HPLC to assess potential solid phase transitions, drying weight loss, and chemical purity.

[0204] After stability testing, all solids were analyzed by HR-XRPD, TGMS, and HPLC. The results of the physicochemical stability tests are reported in Table 7.

[0205] HPLC conditions Automatic sampler temperature: 15℃ Column: Waters Sunfire C18 (100 x 4.6 mm; 3.5 μm).

[0206] Column temperature: 35℃ Flow cell: 10 mm path Gradient: Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Flow rate: 1.0 ml / min Runtime: 11 min Table 7. Results of physicochemical stability tests performed on variants A, B, and C.

[0207] After exposure to 80°C for 1 month and 100°C for 3 days, variant C transformed into variant B. The XRPD plots of variants A and B remained unchanged. Conversely, under all three test conditions, variant C transformed into variant B.

[0208] TGMS analysis showed no obvious moisture absorption, therefore the solid is not hygroscopic.

[0209] The chemical purity of the sample was not affected by exposure to high temperatures and high RH levels for 3 days or 1 month, as indicated by a recovery value close to 100%.

[0210] Example 5: Water Absorption Study Water absorption of variant A The water adsorption of variant A was assessed by exposing the solid material at 25 °C to 80% and 92% RH for 24 hours. Subsequently, the solid was analyzed by HT-XRPD to assess any changes in the crystalline phase, and water absorption was determined by TGMS.

[0211] After 24 hours of exposure to 80% and 92% RH, variant A was physically stable. TGMS analysis showed a mass loss of 0.2% for both samples. Therefore, variant A can be considered non-hygroscopic.

[0212] Water adsorption isotherms of variant A at 25℃ and 40℃ Dynamic vapor adsorption (DVS): Moisture adsorption isotherms were collected on a DVS-1 system from Surface Measurement Systems (London, UK). Typical sample amounts were between 5 and 10 mg of solid material. The relative humidity profile was 40%→0→95%→0→95%→40%, increasing the RH level by 10% per step. The weight equilibrium time was set to a minimum of 60 minutes and a maximum of 6 hours per relative humidity step, with dm / dt of 0.002% / min.

[0213] Dynamic vapor adsorption (DVS) measurements were performed on variant A at 25℃ and 40℃, with the RH curve showing 40%→0→95%→0→95%→40%, increasing by 10% RH at each step.

[0214] Variant A showed no significant water vapor absorption at either 25°C or 40°C. At 95% RH, the highest mass changes were 0.4% and 0.3% at 25°C and 40°C, respectively. Adsorption and desorption cycles were reversible, and no indication of hydrate formation was obtained by DVS measurement. The solid recovered after DVS measurement remained variant A.

[0215] DVS measurement of variants B and C DVS measurements performed on variants B and C yielded similar results to those collected for variant A. Neither phase showed significant water vapor absorption. At 95% RH, the maximum recorded mass increase for both phases was 0.3%.

[0216] After DVS measurement, the XRPD plot of variant B remained unchanged. In contrast, the solid recovered after DVS measurement of variant C was a mixture of variants B and C, which is likely due to the spontaneous conversion of variant C to B at 25 °C.

[0217] Example 5: Stability in Solvents Stability of variant A in solvent Suspensions of variant A were prepared in 23 selected solvents and equilibrated at room temperature (RT) for 4 weeks and at 50 °C for 2 weeks. After equilibration, the solids were separated from the liquid phase, dried under ambient conditions and vacuum (5 mbar / 50 °C), and analyzed by HT-XRPD.

[0218] When the suspension dissolved, the solvent was removed by evaporation under vacuum (initially at 200 mbar / RT, then at 5 mbar / 50 °C). The liquid phase was also evaporated under the same conditions. The residual solids were analyzed by HT-XRPD.

[0219] The experimental details and results of the solvent equilibrium experiments conducted at room temperature and 50°C are shown in Tables 8 and 9, respectively.

[0220] Table 8: Experimental conditions and results of a 4-week solvent equilibrium experiment on variant A at room temperature. The symbol (-) indicates no solids were recovered. The symbol (ly) indicates a low amount of material recovered (low yield). ML is the mother liquor.

[0221] Table 9. Experimental conditions and results of a 2-week solvent equilibrium experiment on variant A at 50°C. The symbol (-) indicates no solids were recovered. The symbol (ly) indicates a low amount of material recovered.

[0222] Stability of variants B and C in solvents Suspensions of variants B and C were prepared in 15 selected solvents and equilibrated at room temperature for 2 weeks and then at 50 °C for 1 week. After equilibration, the solids were separated from the liquid phase, dried under ambient conditions and vacuum (5 mbar / 50 °C), and analyzed by HT-XRPD.

[0223] When the suspension dissolved, the solvent was removed by evaporation under vacuum (initially 200 mbar / RT, then 5 mbar / 50 °C). The liquid phase was also evaporated under the same conditions. The residual solids were analyzed by HT-XRPD.

[0224] The experimental details and results of the solvent equilibrium experiments on variant B at room temperature and 50°C are reported in Tables 10 and 11, respectively.

[0225] The experimental details and results of the solvent equilibrium experiments on variant C at room temperature and 50 °C are reported in Tables 12 and 13, respectively.

[0226] Table 10. Experimental conditions and results of a 2-week solvent equilibrium experiment on variant B at room temperature. The symbol (-) indicates no solids were recovered. The symbol (ly) indicates a low amount of material recovered. The symbol (lc) indicates poor recovery of crystalline material. (S) B (solventization form)

[0227] Table 11. Experimental conditions and results of a 1-week solvent equilibrium experiment on variant B at 50°C. The symbol (-) indicates no solids were recovered. The symbol (ly) indicates a low amount of material recovered.

[0228] Table 12. Experimental conditions and results of a 2-week solvent equilibrium experiment on variant C at room temperature. The symbol (-) indicates no solids were recovered. The symbol (ly) indicates a low amount of material recovered. (S) C (solventization form)

[0229] Table 13. Experimental conditions and results of a 1-week solvent equilibrium experiment on variant C at 50°C. The symbol (ly) indicates a low amount of material recovered. The symbol (-) indicates no solids were recovered.

[0230] Example 6: Stability under granulation simulation experiment Granulation solvent was added dropwise to polymorph A until the solid was fully wetted. The suspension was vortexed between each addition. The suspension was dried under vacuum. The remaining solid form was separated, and the crystallinity was analyzed by XRPD and / or DSC. The granulation solvents tested were water, ethanol, 2-propanol, acetone, and benzyl alcohol. No change in crystallinity was observed.

[0231] Example 7: Stability under compression Using a hydraulic press (13 mm tablet diameter), 100-300 mg of polymorph A was compressed at 10 tons for 5 minutes. The samples were then analyzed by XRPD and DSC to examine for any changes in polymorphism. Analysis showed no change in the material.

[0232] Variant A of the compound having formula (I) was found to be the most stable form. Variant A is physically stable when exposed to high levels of % RH and under prolonged stress conditions. Variant A is stable under compression and granulation simulation experiments. Variant A is stable in most solvents except for chlorinated solvents such as chloroform and dichloromethane, or solvent mixtures containing more than 50% by volume of chlorinated solvents (e.g., dichloromethane and / or chloroform).

[0233] It was found that chlorinated solvents such as chloroform and dichloromethane lead to the formation of variants B and C. Both variants B and C are metastable forms, as variant C transforms into variant B at room temperature or by heating at 50°C, and variant B transforms into variant A above 170°C.

Claims

1. Compound N- (3-(6-amino-5-(2-( N- A crystalline form of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, characterized by The following X-ray powder diffraction pattern, measured at approximately 25 °C and an X-ray wavelength λ of 1.5405 Å, contains one or more representative peaks. With respect to 2θ, these peaks are selected from the group consisting of: 7.8 ± 0.2 °2θ, 9.2 ± 0.2 °2θ, 12.0 ± 0.2 °2θ, 13.6 ± 0.2 °2θ, 15.6 ± 0.2 °2θ, 16.0 ± 0.2 °2θ, 17.8 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 18.7 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 19.9 ± 0.2 °2θ, 22.1 ± 0.2 °2θ, 23.4 ± 0.2 °2θ, 23.9 ± 0.2 °2θ, and 24.8 ± 0.2 °2θ. °2θ, 25.2 ± 0.2 °2θ, 25.5 ± 0.2 °2θ, 27.2± 0.2 °2θ, and 29.6 ± 0.2 °2θ.

2. The crystal form according to claim 1, wherein the crystal form has an X-ray diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG1.

3. The crystal form according to claim 1, characterized in that... The differential thermogravimetric curve was measured by differential scanning calorimetry (DSC) at a heating rate of 10 °C / min, and the curve contains a single endothermic peak starting at approximately 194 °C.

4. The crystal form according to claim 1, wherein the crystal form has a differential scanning calorimetry (DSC) thermal analysis diagram that is substantially the same as that shown in FIG2.

5. The crystal form according to claim 1, wherein the crystal form has a decomposition point greater than 240°C and a drying loss of about 0.3% in the range of 40°C to 200°C, as determined by thermogravimetric analysis.

6. The crystal form according to claim 1, wherein the crystal form has a thermogravimetric analysis (TGA) plot that is substantially the same as that shown in FIG3.

7. The crystal form according to any one of claims 1 to 6, which is substantially composed of type A.

8. The crystal form according to any one of claims 1 to 6, wherein the crystal form is type A in a substantially phase-pure form.

9. Compounds N- (3-(6-amino-5-(2-( N- A crystalline form of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, characterized by The following X-ray powder diffraction pattern, measured at approximately 25 °C and an X-ray wavelength λ of 1.5405 Å, contains one or more representative peaks. With respect to 2θ, these peaks are selected from the following group: 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. °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.

10. The crystal form according to claim 9, wherein the crystal form has an X-ray diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG4.

11. The crystal form according to claim 9, characterized in that... The differential thermogravimetric curve was measured by differential scanning calorimetry at a heating rate of 10 °C / min. The curve includes an endothermic peak starting at approximately 170 °C (corresponding to the melting of variant B), an exothermic peak starting at approximately 175 °C (corresponding to recrystallization into variant A), and an endothermic peak starting at approximately 194 °C (corresponding to the melting of variant A).

12. The crystal form according to claim 9, wherein the crystal form has a differential scanning calorimetry (DSC) thermal analysis diagram that is substantially the same as that shown in FIG5.

13. The crystal form according to claim 9, wherein the crystal form has a decomposition point greater than 240°C and a drying loss of about 0.2% in the range of 40°C to 160°C, as determined by thermogravimetric analysis.

14. The crystal form according to claim 9, wherein the crystal form has a thermogravimetric analysis (TGA) plot that is substantially the same as that shown in FIG6.

15. The crystal form according to any one of claims 9 to 14, which is substantially composed of type B.

16. The crystal form according to any one of claims 9 to 14, wherein the crystal form is type B in a substantially phase-pure form.

17. A pharmaceutical composition comprising the crystal form according to claim 1 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising the crystal form according to claim 9 and a pharmaceutically acceptable carrier.

19. The claim 1 to 16 N- (3-(6-amino-5-(2-( N- The substantially phase-pure crystalline form of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is used for the preparation of a medicament for treating a disorder that is improved by inhibiting BTK.

20. A method for treating a disorder that is improved by inhibiting BTK, the method comprising administering to a patient requiring such treatment an effective amount of any one of claims 1 to 16. N- (3-(6-amino-5-(2-( N- The essentially phase-pure crystalline form of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

21. The method of claim 20 or the use of claim 19, wherein the impairment improved by inhibiting BTK is selected from autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and transplant rejection; wherein antibody production, antigen presentation, cytokine production, or lymphoid organogenesis are abnormal or undesirable diseases; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic spontaneous urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, and type 1 diabetes. Diseases including: type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasser syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism; hematopoietic cancers, including but not limited to multiple myeloma; leukemia; acute... Myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenstrom disease; preferably, diseases or disorders typically improved by BTK inhibition are selected from rheumatoid arthritis; chronic urticaria, preferably chronic spontaneous urticaria; Sjögren's syndrome, multiple sclerosis, or asthma.

22. A method for preparing compounds N- (3-(6-amino-5-(2-( N- A method for obtaining crystal form A of (methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, the method comprising the following steps: a) will N -(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and acrylic anhydride are reacted in a non-chlorinated solvent, optionally in the presence of an inorganic base; and b) Separate the solid crystal form A (e.g., by antisolvent crystallization, cooling crystallization, distillation process or solvent evaporation).

23. The method for preparing crystal form A according to claim 22, wherein the non-chlorinated solvent is ethyl acetate.

24. The method for preparing crystal form A according to claim 22 or 23, wherein form A is separated by distillation.

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