Crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile

Abstract

A crystalline form of compound (I) is disclosed: (I) A pharmaceutical composition comprising the same, a method for treating disorders and pathological conditions mediated by BTK activity using the same, and a method for preparing compound (I) and its crystalline form are also disclosed.

Description

Technology Field

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 964,378 filed January 22, 2020, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile (compound ( I Crystalline form of )), method of use thereof, and compounds including various crystalline forms ( I A method for manufacturing ) is disclosed herein. Compound ( I The crystalline form of ) is an inhibitor of Bruton's tyrosine kinase (BTK). The enzyme BTK is a member of the Tec family of non-receptor tyrosine kinases.

[0003] BTK is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages. BTK plays a role in the development and activation of B cells and is implicated in numerous signaling pathways across a wide range of immune-mediated diseases. BTK activity is associated with the pathogenesis of various disorders and conditions, such as B-cell related blood cancers (e.g., non-Hodgkin lymphoma and B-cell chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis, Sjögren's syndrome, pemphigus, inflammatory bowel disease, lupus, and asthma).

[0004] Compound ( I ) can inhibit BTK and may be useful for the treatment of disorders and pathological conditions related to BTK activity. Compound ( I ) is disclosed in Example 31 of WO 2014 / 039899 and has the following structure:

[0005]

[0006] Here, *C is the stereochemical center. Compound ( I An alternative procedure for producing ) is described in Example 1 of WO 2015 / 127310.

[0007] Compound ( I Solid forms (e.g., crystalline forms) of bioactive compounds such as ) are receiving interest in the pharmaceutical industry, and solid forms possessing specific physical, chemical, or pharmaceutical properties, such as solubility, dissociation, true density, dissolution, melting point, morphology, compression behavior, particle size, flow characteristics, or solid-state stability, may be desirable or even necessary for pharmaceutical development. Crystalline forms arise when a material of the same composition crystallizes into different lattice arrangements, resulting in different thermodynamic properties and stability specific to each crystalline form. Each unique crystalline form is known as a "polymorph."

[0008] Polymorphs of a given substance may have the same chemical composition but may differ from one another in at least one of physical, chemical, and / or pharmaceutical properties such as solubility, dissociation, true density, dissolution, melting point, crystal moisture or morphology, compression behavior, particle size, flow characteristics, and / or solid-state stability. The solid-state form of a bioactive compound often determines its ease of preparation, ease of separation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluid, and bioavailability.

[0009] It is not yet possible to predict the possible solid forms of a compound (e.g., crystalline forms), whether any such forms are suitable for commercial use in pharmaceutical compositions, or which forms or forms will exhibit desirable properties. Since different solid forms (e.g., crystalline forms) can have different properties, a reproducible process for producing a substantially pure solid form is also desirable for bioactive compounds intended for pharmaceutical use.

[0010] Therefore, novel solid forms, including novel crystalline forms useful for treating disorders and pathologies mediated by BTK activity, e.g., compounds ( I ), and a reproducible and scalable method for manufacturing it are required.

[0011] Compound ( I Novel crystalline forms of ), compositions comprising the same, and methods of use and preparation thereof are disclosed herein. In some embodiments, the novel crystalline forms disclosed herein have properties useful for large-scale manufacturing, pharmaceutical formulation, and / or storage. In some embodiments, the novel crystalline forms disclosed herein consist of a single crystalline form. In some embodiments, the crystalline form is substantially pure.

[0012] Some embodiments of the present invention include pharmaceutically acceptable excipients; and compounds ( I The invention relates to a pharmaceutical composition comprising at least one crystalline form selected from the crystalline forms of ). In some embodiments, at least one crystalline form is a compound ( I ) is a crystalline form A. In some embodiments, at least one crystalline form is a compound ( I ) is the crystalline form B. In some embodiments, at least one crystalline form is the compound ( I It is the crystalline form of ) C.

[0013] Some embodiments of the present invention are compounds (in mammals requiring BTK inhibition) I The present invention relates to a method for inhibiting BTK in mammals by administering a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of ). In some embodiments, at least one crystalline form is a compound ( I ) is a crystalline form A. In some embodiments, at least one crystalline form is a compound ( I) is the crystalline form B. In some embodiments, at least one crystalline form is the compound ( I It is the crystalline form of ) C.

[0014] In some embodiments, mammals requiring BTK inhibition suffer from BTK-mediated diseases. In some embodiments, diseases mediated by BTK include pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, alopecia areata, vitiligo, pyoderma gangrenosolitis, membranous pemphigus, acquired epidermolysis bullosa, Stevens-Johnson syndrome, TEN toxic epidermal necrolysis, drug rash, alopeciatic folliculitis, psoriatic pseudofolliculitis, leukocytoclastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, acne, mycosis fungoides, Sweet syndrome, inflammatory bowel disease, arthritis, lupus, lupus nephritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, Sjögren's syndrome, multiple sclerosis, ankylosing spondylitis, scleroderma, Wegener's granulomatosis, psoriasis, asthma, colitis, conjunctivitis, dermatitis, uveitis, eczema, diffuse large B cells It is selected from lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmocytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) giant B-cell lymphoma, non-Hodgkin lymphoma, intravascular giant B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, and lymphomatous granulomatosis.

[0015] In some embodiments, the disease mediated by BTK is pemphigus vulgaris. In some embodiments, the disease mediated by BTK is pemphigus foliaceus. In some embodiments, the disease mediated by BTK is immune thrombocytopenia. In some embodiments, the disease mediated by BTK is lupus nephritis.

[0016] In some embodiments, the mammal requiring BTK inhibition is a human. In some embodiments, the mammal requiring BTK inhibition is a dog.

[0017] Compound ( I A method for producing at least one crystalline form selected from the crystalline forms of ) is also disclosed herein. Some embodiments of the present invention are such that at least one crystalline form is a compound ( I The present invention relates to the above method, wherein crystalline form A of ). Some embodiments of the present invention are such that at least one crystalline form is a compound ( I The present invention relates to the above method, wherein the crystalline form B of ) is ) I This relates to the above method, which is a crystalline form C of ). Brief explanation of the drawing

[0018] Fig. 1 A compound (referred to herein as crystalline form A), which represents a degree 2θ (2-theta) on the X-axis and relative intensity on the Y-axis. I This shows the X-ray powder diffraction pattern for crystalline form A of ). Fig. 2 is a compound ( I This shows the differential scanning calorimetry (DSC) thermogram for crystalline form A of ). Fig. 3 silver compound ( I This shows the thermogravimetric (TG-FTIR) thermal curve coupled with Fourier transform infrared spectroscopy for the crystalline form A of ). Fig. 4a is a compound (referred to herein as crystalline form B), comprising 95% to 99% of (E)-isomers, representing 2θ (2-theta) on the X-axis and relative intensity on the Y-axis. I This shows the X-ray powder diffraction pattern for the crystalline form B of ). Fig. 4bis a compound containing more than 99% (E)-isomers, representing 2θ (2-theta) on the X-axis and relative intensity on the Y-axis ( I This shows the X-ray powder diffraction pattern for the crystalline form B of ). Fig. 5a is a compound containing 95% to 99% (E)-isomers ( I This shows the differential scanning calorimetry (DSC) thermogram for crystalline form B of ). Fig. 5b is a compound containing more than 99% (E)-isomers ( I This shows the differential scanning calorimetry (DSC) thermogram for crystalline form B of ). Fig. 6a is a compound containing 95% to 99% (E)-isomers ( I This shows the thermogravimetric (TG-FTIR) thermal curve coupled with Fourier transform infrared spectroscopy for the crystalline form B of ). Fig. 6b is a compound containing more than 99% (E)-isomers ( I This shows the thermogravimetric (TG-FTIR) thermal curve coupled with Fourier transform infrared spectroscopy for the crystalline form B of ). do 7 A compound (referred to herein as crystalline form C, representing 2θ (2-theta) on the X-axis and relative intensity on the Y-axis) I This shows the X-ray powder diffraction pattern for the crystalline form C of ). Fig. 8 Silver shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) thermal curve for crystalline form C with a scanning rate of 15℃ / min. Fig. 9 Figure 1 shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) thermal curve for crystalline form C with a scanning rate of 10℃ / min. Fig. 10 Figure 1 shows the thermogravimetric (TG-FTIR) thermal curve coupled with Fourier transform infrared spectroscopy for the crystalline form C. Fig. 11It represents a single crystal structure for the crystalline form C. Specific details for implementing the invention

[0019] definition:

[0020] As used herein, unless otherwise noted, the singular form (“a” or “an”) of an entity refers to one or more such entities, for example, “compound” refers to one or more compounds or at least one compound. As such, the singular form, “one or more,” and “at least one” may be used interchangeably herein.

[0021] As used herein, the term “approximately” means roughly, within a range, generally, or to an extent. When the term “approximately” is used in relation to a numerical range, it modifies the range by extending the boundaries above and below the stated numerical value. Generally, the term “approximately” is used to modify a value that is 5% above and below the value specified herein.

[0022] As used herein, "compound ( I )" is (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile, (S)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile, or It refers to the (E) isomer, (Z) isomer, or mixture of (E) and (Z) isomers of the (R) and (S) enantiomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile, which has the following structure:

[0023]

[0024] Here, *C is the stereochemical center.

[0025] Compound ( I When ) is represented as (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile, it may contain the corresponding (S) enantiomer as less than 1 weight% of impurities. Thus, compound ( I When ) is represented as a mixture of (R) and (S) enantiomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile, the amount of (R) or (S) enantiomer in the mixture is greater than 1 weight%. Similarly, compound ( I If ) is represented as an (E) isomer, it may contain the corresponding (Z) isomer as less than 1 weight percent of impurities. Therefore, compound ( I When ) is represented as a mixture of (E) and (Z) isomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile, the amount of (E) or (Z) isomer in the mixture is greater than 1 weight%.

[0026] As used herein, a compound containing "[Y]% (E)-isomer ( I The crystalline form [X]" of ) is the compound of the above crystalline form ( I This means that [Y]% of ) is the (E)-isomer.

[0027] In this institution, compounds ( I) may refer to "drug," "activator," "therapeutic active agent," or "API."

[0028] As used herein, "substantially pure" with respect to geometric isomer forms is a compound (in which more than 70 weight percent of the compound exists in a given isomer form) I It refers to compounds such as ). For example, "compound ( I The crystalline form A of ) is compound ( I The phrase “is a substantially pure (E) isomer of )” refers to the compound ( I A compound in which at least 70 weight percent of the crystalline form A of ) is the isomer form (E) I Refers to the crystalline form A of ), and "compound ( I The crystalline form A of ) is compound ( I The phrase “is a substantially pure (Z) isomer of )” refers to the compound ( I A compound in which at least 70 weight percent of the crystalline form A of ) is the (Z) isomer form ( I It refers to the crystalline form A of ). In some embodiments, the compound ( I At least 80 weight percent of the crystalline form of ) is of the (E) form or compound ( I At least 80 weight percent of the crystalline form of ) is the (Z) form. In some embodiments, the compound ( I At least 85 weight percent of the crystalline form of ) is of the (E) form or compound ( I At least 85 weight percent of the crystalline form of ) is the (Z) form. In some embodiments, the compound ( I At least 90 weight percent of the crystalline form of ) is of the (E) form or compound ( I At least 90 weight percent of the crystalline form of ) is the (Z) form. In some embodiments, the compound ( I At least 95 weight percent of the crystalline form of ) is of the (E) form or compound ( IAt least 95 weight percent of the crystalline form of ) is the (Z) form. In some embodiments, the compound ( I At least 97 weight% or at least 98 weight% of the crystalline form of ) is of form (E), or at least 97 weight% or at least 98 weight% of the crystalline form of compound (I) is of form (Z). In some embodiments, compound ( I At least 99 weight percent of the crystalline form of ) is of the (E) form or compound ( I At least 99 weight percent of the crystalline form of ) is the (Z) form. The relative amounts of (E) and (Z) isomers in the solid mixture can be determined according to standard methods and techniques known in the art.

[0029] As used herein, "pharmaceutical acceptable excipients" refers to carriers or excipients useful for preparing pharmaceutical compositions. For example, pharmaceutical acceptable excipients include carriers and excipients that are generally safe and are generally considered acceptable for mammalian pharmaceutical uses.

[0030] As used herein, the terms “polymorph,” “crystalline form,” “crystalline form,” and “form” refer interchangeably to a solid having a specific molecular packing arrangement in a crystal lattice. Crystalline forms may be identified and distinguished from one another by at least one characterization technique, such as X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor deposition (DVS), and / or thermogravimetric analysis (TGA). Accordingly, as used herein, the term “compound ( IThe crystalline form [X]" of ) refers to a unique crystalline form that can be identified and distinguished from other forms by at least one characterization technique including, for example, X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor deposition (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline form of the present invention is characterized by an X-ray powder diffraction pattern having at least one signal at at least one specified 2-theta value (º 2θ).

[0031] As used herein, the “therapeutic effective amount” of the compounds disclosed herein refers to the amount of compound that elicits a biological or medical response in a subject. The therapeutic effective amount will vary depending on the therapeutic purpose and will be identifiable by those skilled in the art (e.g., see Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0032] As used herein, the terms “inhibit,” “inhibit,” or “inhibiting” refer to the reduction or suppression of a given pathological condition, symptom, or disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0033] As used herein, the terms “treat,” “treating,” or “treatment,” when used in relation to a disorder or condition, include any effect, e.g., alleviation, reduction, adjustment, improvement, or elimination that brings about an improvement in said disorder or condition. Any improvement or alleviation of the severity of any symptom of said disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0034] As used herein, "mammals" refers to domesticated animals (e.g., dogs, cats, and horses) and humans. In some embodiments, mammals are humans. In some embodiments, mammals are canids.

[0035] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0036] As used herein, the term "TGA" refers to the analytical method of thermogravimetric analysis (also referred to as thermogravimetric analysis).

[0037] As used herein, the term "TG-FTIR" refers to an analytical method of thermogravimetric measurement coupled with Fourier transform infrared spectroscopy.

[0038] As used herein, the term "XRPD" refers to a method for the analytical characterization of X-ray powder diffraction. XRPD patterns can be recorded under ambient conditions in transmission or reflection geometry using a diffractometer.

[0039] As used herein, the terms “X-ray powder diffraction,” “X-ray powder diffraction pattern,” and “XRPD pattern” refer to an experimentally obtained pattern plotting signal position (horizontal coordinate) versus signal intensity (vertical coordinate). For crystalline materials, the X-ray powder diffraction may include at least one signal, each identified by an angle value as measured in units of 2θ (°2θ), displayed in the horizontal coordinate of the X-ray powder diffraction, which can be expressed as “... signal at 2-theta”, “... [a] signal at 2-theta value(s)” and / or “signal at at least ... 2-theta value(s) selected from”.

[0040] As used herein, the term "... X-ray powder diffraction pattern having a signal at a value of 2-theta" refers to an XRPD pattern including an X-ray reflection position (°2θ) as measured and observed in X-ray powder diffraction experiments.

[0041] As used herein, the term "signal" refers to a point in an XRPD pattern where the intensity, as measured in count units, is a local maximum. Those skilled in the art will recognize that at least one signal may overlap in an XRPD pattern and may not be clear, for example, to the naked eye. Those skilled in the art will recognize that some methods recognized in the art, such as the Rietveld refining method, can determine whether a signal is present in the pattern and are suitable for such determination.

[0042] As used herein, the terms "signal at ... 2-theta", "signal at [a] 2-theta value[] of ..." and "signal at at least ... 2-theta value(s) selected from ..." refer to the X-ray reflection position (º 2θ) as measured and observed in X-ray powder diffraction experiments. In some embodiments, the repeatability of the angle value is in the range of ± 0.2° 2θ, that is, the angle value may be the mentioned angle value + 0.2 2-theta, the angle value - 0.2 2-theta, or any value between these two endpoints (angle value + 0.2 2-theta and angle value - 0.2 2-theta). It is well known to those skilled in the art that there may be variability in the measurement of X-ray powder diffraction signal values. As such, those skilled in the art will recognize that there may be a variability of up to ± 0.2° 2θ of the signal value for the same signal in different samples. Additionally, it is well known to those skilled in the art that there may be variability in the measurement of relative signal intensity in X-ray powder diffraction experiments. For example, non-limiting factors that may affect relative signal intensity include sample thickness and preferred orientation (e.g., crystalline grains are not randomly distributed).

[0043] As used herein, an X-ray powder diffraction is “substantially similar to that of the [specific] figure when at least 90% of the signal in two diffraction figures, e.g., at least 95%, at least 98%, or at least 99%, is the same ± 0.2 °2θ.” In determining “substantially similar,” those skilled in the art will understand that there may be variations in intensity and / or signal position in XRPD diffraction figures even for the same crystalline form. Accordingly, those skilled in the art will understand that the maximum signal value in the XRPD diffraction figure (in the units of °2θ as mentioned herein) generally means such a reported value ± 0.2 °2θ of the reported value (the deviation discussed above recognized in the art).

[0044] As mentioned above, the compound ( I A novel crystalline form of ) is described herein. This novel crystalline form may be an inhibitor of BTK. BTK inhibitors are useful for the treatment of diseases mediated by BTK, such as, for example, pemphigus vulgaris, pemphigus foliaceus, and immune thrombocytopenia.

[0045] Embodiment:

[0046] Non-limiting embodiments of the present invention include the following:

[0047] 1. Compound ( I Crystalline form A of )

[0048] ( I )

[0049] (In the above formula, C* is the stereochemical center).

[0050] 2. Crystalline form A, characterized in that, in embodiment 1, the X-ray powder diffraction pattern has signals at at least three 2-theta values ​​selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2.

[0051] 3. Crystalline form A, characterized in that, in embodiment 1 or 2, it features an X-ray powder diffraction pattern substantially similar to that of FIG. 1.

[0052] 4. Crystalline form A, characterized in any one of embodiments 1 to 3, having a DSC thermogram having a peak endothermic (melting temperature) at about 146 ℃ to about 147 ℃.

[0053] 5. Crystalline form A, characterized by a DSC thermogram indicating melting initiation at about 140.6 ℃ to about 141.2 ℃ in any one of embodiments 1 to 4.

[0054] 6. Crystalline form A, characterized by a mass loss of less than 1.0 wt% at 25 ℃ to 200 ℃ by thermogravimetric analysis in any one of embodiments 1 to 5.

[0055] 7. Crystalline form A, characterized by having a water content of less than 1% when stored at 95% relative humidity (RH) in any one of embodiments 1 to 6.

[0056] 8. In any one of embodiments 1 to 7, the compound ( I Crystalline form A, of which at least 95% is an isomer of (E).

[0057] 9. A compound prepared by a method comprising the following ( ICrystalline form A of )

[0058] A step of forming a solution by adding isopropyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile;

[0059] A step of stirring the solution to form a precipitate; and

[0060] Step of isolating crystalline form A by filtration.

[0061] 10. Compounds ( I Crystalline form B of )

[0062] ( I )

[0063] (In the above formula, C* is the stereochemical center).

[0064] 11. Crystalline form B, characterized in that, in embodiment 10, the X-ray powder diffraction pattern has signals at at least three 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.0 ± 0.2, and 22.9 ± 0.2.

[0065] 12. In Embodiment 10 or Embodiment 11, the compound ( I Crystalline form B, of which at least >99% is an isomer of (E).

[0066] 13. In Embodiment 10 or Embodiment 11, the compound ( I 95% to 99% of ) is the crystalline form B, which is an isomer of (E).

[0067] 14. Crystalline form B, characterized in that, in any one of embodiments 10 to 12, the X-ray powder diffraction pattern is substantially similar to that of FIG. 4b.

[0068] 15. Crystalline form B, characterized in that, in any one of embodiment 10, embodiment 11, or embodiment 13, the X-ray powder diffraction pattern is substantially similar to that of FIG. 4a.

[0069] 16. Crystalline form B, characterized in any one of embodiments 10 to 12 or embodiment 14, having a DSC thermogram having a peak endothermic (melting temperature) at about 144 ℃ to about 146 ℃.

[0070] 17. Crystalline form B, characterized by a DSC thermogram indicating melting initiation at about 139.3 ℃ in any one of embodiments 10 to 12, embodiment 14, or embodiment 16.

[0071] 18. Crystalline form B, characterized in any one of embodiment 10, embodiment 11, embodiment 13, or embodiment 15, having a DSC thermogram having a peak endothermic (melting temperature) at about 141 ℃ to about 142 ℃.

[0072] 19. Crystalline form B, characterized by a DSC thermogram indicating melting initiation at about 131.8 ℃ to about 132.4 ℃ in any one of embodiments 10, 11, 13, 15, or 18.

[0073] 20. Crystalline form B, characterized by a water content of less than 1.3% when stored at 95% relative humidity (RH) in any one of embodiments 10 to 19.

[0074] 21. A compound prepared by a method comprising the following ( I Crystalline form B of )

[0075] A step of forming a solution by adding ethyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile;

[0076] A step of seeding sodium chloride into a solution and stirring the solution to obtain a suspension;

[0077] Step of isolating crystalline form B by filtration of the suspension.

[0078] 22. A compound prepared by a method comprising the following ( I Crystalline form B of )

[0079] A step of forming a solution or slurry by adding ethanol to form C of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile;

[0080] Compound in solution or slurry ( I Step of seeding the seed determination of form B of ); and

[0081] Compound by filtration ( I Step of isolating crystalline form B of ).

[0082] 23. Compounds ( I Crystalline form of ) C:

[0083] ( I )

[0084] (In the above formula, C* is the stereochemical center).

[0085] 24. In embodiment 23, the crystalline form C is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2.

[0086] 25. Crystalline form C, characterized in that, in embodiment 23 or embodiment 24, the X-ray powder diffraction pattern is substantially similar to that of FIG. 7.

[0087] 26. In any one of embodiments 23 to 25, the DSC thermogram is characterized by having a peak endothermic (melting temperature) at about 118.5 °C to about 119 °C, and the DSC scanning rate is 15 Crystalline form C, with a temperature of ℃ / min.

[0088] 27. In any one of embodiments 23 to 26, a crystalline form C is characterized by a DSC thermogram indicating melting initiation at about 115.6 ℃ to about 116 ℃, wherein the DSC scanning rate is 15 ℃ / min.

[0089] 28. In any one of embodiments 23 to 27, a crystalline form C is characterized by a DSC thermogram having a peak endothermic (melting temperature) at about 120.5 ℃ to about 121 ℃, wherein the DSC scanning rate is 10 ℃ / min.

[0090] 29. In any one of embodiments 23 to 28, a crystalline form C is characterized by a DSC thermogram indicating melting initiation at about 118 ℃ to about 118.5 ℃, wherein the DSC scanning rate is 10 ℃ / min.

[0091] 30. In any one of embodiments 23 to 29, the compound ( I At least 95% of ) is the crystalline form C, which is an (E) isomer.

[0092] 31. A crystalline form C characterized by a P-1 space group in any one of embodiments 23 to 30.

[0093] 32. In any one of embodiments 23 to 31, a crystalline form C characterized by the following unit cell dimensions at 200(2) K:

[0094] a = 10.6741 Å α = 93.654°

[0095] b = 12.7684 Å β= 104.400°

[0096] c = 14.5287 Å γ = 105.476°.

[0097] 33. A compound prepared by a method comprising the following ( I Crystalline form of ) C:

[0098] A step of forming a solution by adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile;

[0099] Compound in solution ( I A step of seeding the crystalline form B of ) to form a mixture and stirring the mixture to obtain a slurry; and

[0100] A step of filtering the slurry to isolate the crystalline form C.

[0101] 34.

[0102] A compound selected from the crystalline form of any one of embodiments 1 to 33 ( I At least one crystalline form of ); and

[0103] A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

[0104] 35. In Embodiment 34, the pharmaceutical composition is in the form of a solid oral composition.

[0105] 36. A pharmaceutical composition according to Embodiment 34 or Embodiment 35, wherein the pharmaceutical composition is in the form of a tablet or a capsule.

[0106] 37. A method for inhibiting Bruton's tyrosine kinase (BTK) in mammals, comprising the step of administering a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of embodiments 1 to 33 to a mammal requiring BTK inhibition.

[0107] 38. A method for treating a disease mediated by Bruton's tyrosine kinase (BTK) in a mammal requiring treatment for such disease, comprising the step of administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of embodiments 1 to 33.

[0108] 39. A method for treating pemphigus vulgaris or pemphigus foliaceus in mammals requiring treatment for pemphigus vulgaris or pemphigus foliaceus, comprising the step of administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of embodiments 1 to 33.

[0109] 40. A method for treating immune thrombocytopenia in mammals requiring treatment for immune thrombocytopenia, comprising the step of administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of embodiments 1 to 33.

[0110] 41. A method in any one of embodiments 37 to 40, wherein the mammal is a human.

[0111] Compound ( I Crystalline form A of )

[0112] In some embodiments, the present invention relates to a compound ( I Provides crystalline form A of ):

[0113] (I )

[0114] Here, *C is the stereochemical center.

[0115] Figure 1 shows a compound ( I This shows the X-ray powder diffraction pattern of crystalline form A of ). In FIG. 1, the XRPD pattern corresponds to crystalline form A having a small amount of crystalline form B, which is further described below.

[0116] Figure 2 shows a compound ( I Shows the DSC thermogram of crystalline form A of ). In some embodiments, compound ( I Crystalline form A of ) is characterized by a DSC thermogram having a peak endothermic (melting temperature) at about 146 °C to about 147 °C. In some embodiments, compound ( I Crystalline form A of ) is characterized by a DSC thermogram indicating the initiation of melting / decomposition at about 140.6 °C to about 141.2 °C. In some embodiments, the compound ( I Crystalline form A of ) is characterized by a DSC thermogram indicating melting initiation at about 140.6 °C to about 141.2 °C. In some embodiments, the associated enthalpy is about 52 J / g (ΔH = 52 J / g).

[0117] In some embodiments, the compound ( I The crystalline form A of ) features a DSC thermogram substantially similar to that of Fig. 2.

[0118] In some embodiments, the compound ( I Crystalline form A of ) features a thermogravimetric (TG-FTIR) thermal curve coupled to Fourier transform infrared spectroscopy substantially similar to that of FIG. 3. In some embodiments, the compound ( ICrystalline form A of ) is characterized by a mass loss of less than 1.0 wt% at 25 °C to 200 °C by thermogravimetric analysis. In some embodiments, this mass loss corresponds to the loss of isopropyl acetate released near the melting temperature. In some embodiments, decomposition is observed at higher temperatures, for example, substantially as shown in FIG. 3 (initiated at about 220 °C to about 230 °C).

[0119] In some embodiments, the compound ( I Crystalline form A of ) has a water content of less than 1% when stored at 85% relative humidity (RH).

[0120] In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having a signal substantially similar to those mentioned in Table 1.

[0121] [Table 1]

[0122]

[0123]

[0124] In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at 2-theta of 5.6 ± 0.2. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at 2-theta of 12.7 ± 0.2. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at 16.5 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at 17.0 ± 0.2 degrees 2-theta. In some embodiments, the compound (I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at 17.7 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at 18.7 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at 19.2 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at 20.7 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at 22.2 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at 24.4 ± 0.2 degrees 2-theta.

[0125] In some embodiments, the compound ( I Crystalline form A of ) is characterized by X-ray powder diffraction patterns having signals at 2-theta values ​​of 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having signals at at least nine 2-theta values ​​selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, the compound ( ICrystalline form A of ) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2-theta values ​​selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, the compound ( ICrystalline form A of ) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at at least two 2-theta values ​​selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2. In some embodiments, the compound ( I Crystalline form A of ) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2.

[0126] In some embodiments, the compound ( I The crystalline form A of ) features an X-ray powder diffraction pattern substantially similar to that of Fig. 1.

[0127] In some embodiments, the present invention comprises a compound (I A method for preparing a crystalline form A of ) is provided: a step of adding isopropyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile to form a solution; in some embodiments, the method further comprises a step of stirring the solution to form a precipitate. In some embodiments, the method further comprises a step of isolating the crystalline form A by filtration.

[0128] In some embodiments, the present invention relates to a compound prepared by a method comprising the following ( I ) provides a crystalline form A: a step of adding isopropyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile to form a solution; in some embodiments, the method further comprises a step of stirring the solution to form a precipitate. In some embodiments, the method further comprises a step of isolating the crystalline form A by filtration.

[0129] Compound ( I Crystalline form B of )

[0130] In some embodiments, the present invention relates to a compound ( I Provides crystalline form B of ):

[0131] ( I )

[0132] Here, *C is the stereochemical center.

[0133] FIG. 4a is a compound containing 95% to 99% (E)-isomers ( IThis shows the X-ray powder diffraction pattern for the crystalline form B of ). In Fig. 4a, the XRPD pattern is of the amorphous compound ( in ethyl acetate) I It corresponds to crystalline form B obtained without an NaCl seed using seed crystals of crystalline form A and B, which are added to a stirred solution of ) and stirred overnight (which results in crystallization and the formation of crystalline form B).

[0134] FIG. 4b is a compound containing >99% (E)-isomers ( I This shows the X-ray powder diffraction pattern for crystal form B of ). In Fig. 4b, the XRPD pattern is, compound ( in ethanol I It corresponds to crystalline form B obtained without an NaCl seed using a seed crystal of crystalline form B, which is added to a stirred slurry of form C and stirred overnight (which results in crystallization and the formation of crystalline form B containing more than 99% of (E)-isomers).

[0135] Crystalline form A can transition to crystalline form B over time. Therefore, crystalline form B can be thermodynamically more stable than crystalline form A at room temperature.

[0136] Crystalline form C can transition to crystalline form B over time. Therefore, crystalline form B can be thermodynamically more stable than crystalline form C at room temperature.

[0137] FIG. 5a is a compound containing 95% to 99% (E)-isomers ( I This shows the DSC thermogram of the crystalline form B of ).

[0138] In some embodiments, the compound ( I Crystalline form B of ) is characterized by a DSC thermogram having a peak endothermic (melting temperature) at about 141 °C to about 142 °C. In some embodiments, the compound ( ICrystalline form B of ) is characterized by a DSC thermogram indicating the initiation of melting / decomposition at about 131.8 °C to about 132.4 °C. In some embodiments, the compound ( I Crystalline form B of ) is characterized by a DSC thermogram indicating melting initiation at about 131.8 °C to about 132.4 °C. In some embodiments, the associated enthalpy is about 54.9 J / g (ΔH = 54.9 J / g).

[0139] In some embodiments, a compound comprising 95% to 99% (E)-isomer ( I Crystalline form B of ) is characterized by a DSC thermogram having a peak endothermic (melting temperature) at about 141 °C to about 142 °C. In some embodiments, a compound ( comprising 95% to 99% of (E)-isomer) I Crystalline form B of ) is characterized by a DSC thermogram indicating melting / decomposition initiation at about 131.8 °C to about 132.4 °C. In some embodiments, a compound ( comprising 95% to 99% of (E)-isomer) I Crystalline form B of ) is characterized by a DSC thermogram indicating melting initiation at about 131.8 °C to about 132.4 °C. In some embodiments, the associated enthalpy is about 54.9 J / g (ΔH = 54.9 J / g).

[0140] In some embodiments, the compound ( I Crystalline form B of ) features a DSC thermogram substantially similar to that of FIG. 5a. In some embodiments, a compound ( comprising 95% to 99% of the (E)-isomer) I The crystalline form B of ) features a DSC thermogram substantially similar to that of Fig. 5a.

[0141] Figure 5b shows a DSC thermogram of crystalline form B containing >99% (E)-isomers.

[0142] In some embodiments, the compound ( I The crystalline form of ) is characterized by a DSC thermogram having a peak endothermic (melting temperature) at about 144 °C to about 146 °C. In some embodiments, the compound ( I Crystalline form B of ) is characterized by a DSC thermogram indicating melting initiation at approximately 139.3 °C. In some embodiments, the associated enthalpy is approximately 65.5 J / g (ΔH = 65.5 J / g).

[0143] In some embodiments, a compound containing >99% (E)-isomers ( I The crystalline form of ) is characterized by a DSC thermogram having a peak endothermic (melting temperature) at about 144 °C to about 146 °C. In some embodiments, a compound ( comprising >99% of (E)-isomers) I Crystalline form B of ) is characterized by a DSC thermogram indicating melting initiation at approximately 139.3 °C. In some embodiments, the associated enthalpy is approximately 65.5 J / g (ΔH = 65.5 J / g).

[0144] In some embodiments, the compound ( I The crystalline form B of ) features a DSC thermogram substantially similar to that of FIG. 5b. In some embodiments, a compound ( comprising >99% (E)-isomer) I The crystalline form B of ) features a DSC thermogram substantially similar to that of Fig. 5b.

[0145] In some embodiments, the compound ( I Crystalline form B of ) features a thermogravimetric (TG-FTIR) thermal curve coupled to Fourier transform infrared spectroscopy substantially similar to that of FIG. 6a. In some embodiments, a compound ( comprising 95% to 99% of the (E)-isomer) ICrystalline form B of ) features a thermogravimetric (TG-FTIR) thermal curve coupled to Fourier transform infrared spectroscopy substantially similar to that in Fig. 6a.

[0146] In some embodiments, the compound ( I Crystalline form B of ) is characterized by a mass loss of less than 0.8 wt% at 25 °C to 162 °C by thermogravimetric analysis. In some embodiments, in addition to the above mass loss, there is an additional mass loss of less than 0.8 wt% at 162 °C to 250 °C by thermogravimetric analysis. In some embodiments, this additional mass loss corresponds to the removal of ethyl acetate. In some embodiments, decomposition is observed at higher temperatures, for example, substantially as illustrated in FIG. 6a (initiated at about 250 °C to about 253 °C).

[0147] In some embodiments, a compound comprising 95% to 99% (E)-isomer ( I Crystalline form B of ) is characterized by a mass loss of less than 0.8 wt% at 25 °C to 162 °C by thermogravimetric analysis. In some embodiments, in addition to the above mass loss, there is an additional mass loss of less than 0.8 wt% at 162 °C to 250 °C by thermogravimetric analysis. In some embodiments, this additional mass loss corresponds to the removal of ethyl acetate. In some embodiments, decomposition is observed at higher temperatures, for example, substantially as illustrated in FIG. 6a (initiated at about 250 °C to about 253 °C).

[0148] In some embodiments, the compound ( ICrystalline form B of ) features a thermogravimetric (TG-FTIR) thermal curve coupled to Fourier transform infrared spectroscopy substantially similar to that of FIG. 6b. In some embodiments, crystalline form B of compound (I) containing >99% (E)-isomer features a thermogravimetric (TG-FTIR) thermal curve coupled to Fourier transform infrared spectroscopy substantially similar to that of FIG. 6b.

[0149] In some embodiments, a compound comprising 95 to 99% (E)-isomers ( I Crystalline form B of ) is characterized by a mass loss of less than 0.7 wt% at 25 °C to 162 °C by thermogravimetric analysis. In some embodiments, in addition to the above mass loss, there is an additional mass loss of less than 0.7 wt% at 162 °C to 250 °C by thermogravimetric analysis. In some embodiments, this additional mass loss corresponds to the removal of ethanol. In some embodiments, decomposition is observed at higher temperatures, for example, substantially as illustrated in FIG. 6a (initiated at about 250 °C to about 253 °C).

[0150] In some embodiments, a compound containing >99% (E)-isomers ( I Crystalline form B of ) is characterized by a mass loss of less than 0.5 wt% at 25 °C to 162 °C as determined by thermogravimetric analysis. In some embodiments, in addition to the above mass loss, there is an additional mass loss of less than 0.5 wt% at 162 °C to 250 °C as determined by thermogravimetric analysis. In some embodiments, this additional mass loss corresponds to the removal of ethanol. In some embodiments, decomposition is observed at higher temperatures, for example, substantially as illustrated in FIG. 6b (initiated at about 250 °C to about 253 °C).

[0151] In some embodiments, the compound ( ICrystalline form B of ) is characterized by a water content of less than 1.3% when stored at 95% relative humidity (RH). In some embodiments, a compound comprising 95% to 99% of the (E)-isomer ( I Crystalline form B of ) is characterized by a water content of less than 1.3% when stored at 95% relative humidity (RH).

[0152] In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having a signal substantially similar to those mentioned in Table 2A. In some embodiments, a compound comprising 95% to 99% of the (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having a signal substantially similar to those mentioned in Table 2A.

[0153] [Table 2A]

[0154]

[0155]

[0156] In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 10.8 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 15.3 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 16.3 ± 0.2 degrees 2-theta. In some embodiments, the compound ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 2-theta with 17.9 ± 0.2 degrees. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 18.4 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 18.7 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 22.9 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I The crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 23.1 ± 0.2 degrees 2-theta.

[0157] In some embodiments, a compound comprising 95% to 99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 10.8 ± 0.2 degrees 2-theta. In some embodiments, a compound comprising 95% to 99% of the (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 15.3 ± 0.2 degrees 2-theta. In some embodiments, a compound comprising 95% to 99% of the (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 16.3 ± 0.2 degrees 2-theta. In some embodiments, a compound comprising 95% to 99% of the (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 17.9 ± 0.2 degrees 2-theta. In some embodiments, a compound comprising 95% to 99% of the (E)-isomer ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 18.4 ± 0.2 degrees 2-theta. In some embodiments, a compound comprising 95% to 99% of the (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 18.7 ± 0.2 degrees 2-theta. In some embodiments, a compound comprising 95% to 99% of the (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 22.9 ± 0.2 degrees 2-theta. In some embodiments, a compound comprising 95% to 99% of the (E)-isomer ( I The crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 23.1 ± 0.2 degrees 2-theta.

[0158] In some embodiments, the compound ( I Crystalline form B of ) is characterized by X-ray powder diffraction patterns having signals at 2-theta values ​​of 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, the compound ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at at least two 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, the compound ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2.

[0159] In some embodiments, a compound comprising 95% to 99% (E)-isomer ( I Crystalline form B of ) is characterized by X-ray powder diffraction patterns having signals at 2-theta values ​​of 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, a compound comprising 95% to 99% of (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, a compound comprising 95% to 99% of (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, a compound comprising 95% to 99% of (E)-isomer ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, a compound comprising 95% to 99% of (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, a compound comprising 95% to 99% of (E)-isomers ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, a compound comprising 95% to 99% of (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at at least two 2-theta values ​​selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2. In some embodiments, a compound comprising 95% to 99% of (E)-isomer ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected from 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.9 ± 0.2, and 23.1 ± 0.2.

[0160] In some embodiments, the compound ( I Crystalline form B of ) features an X-ray powder diffraction pattern substantially similar to that of FIG. 4a. In some embodiments, a compound comprising 95% to 99% of the (E)-isomer ( I The crystalline form B of ) features an X-ray powder diffraction pattern substantially similar to that of Fig. 4a.

[0161] In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having a signal substantially similar to those mentioned in Table 2B. In some embodiments, a compound containing >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having a signal substantially similar to those mentioned in Table 2B.

[0162] [Table 2B]

[0163]

[0164]

[0165]

[0166] In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern at 4.2 ± 0.2 degrees 2-theta. In some embodiments, the compound ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 2-theta of 5.1 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 10.8 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 15.3 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 16.3 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 2-theta with 17.9 ± 0.2 degrees. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 18.4 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 18.7 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 19.2 ± 0.2 θ. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 21.2 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I The crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 22.0 ± 0.2 degrees 2-theta.

[0167] In some embodiments, a compound containing >99% (E)-isomers ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern at 4.2 ± 0.2 degrees 2-theta. In some embodiments, a compound containing >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 2-theta of 5.1 ± 0.2. In some embodiments, a compound ( comprising >99% of (E)-isomer) I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 2-theta with 10.8 ± 0.2 degrees. In some embodiments, a compound containing >99% of (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 15.3 ± 0.2 degrees 2-theta. In some embodiments, a compound ( comprising >99% of (E)-isomer) I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 16.3 ± 0.2 degrees 2-theta. In some embodiments, a compound containing >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 2-theta, 17.9 ± 0.2. In some embodiments, a compound containing >99% of (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 18.4 ± 0.2 degrees 2-theta. In some embodiments, a compound containing >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 2-theta, 18.7 ± 0.2. In some embodiments, a compound ( comprising >99% of (E)-isomer) I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 19.2 ± 0.2 θ. In some embodiments, a compound ( comprising >99% of (E)-isomers) ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 21.2 ± 0.2 degrees 2-theta. In some embodiments, a compound containing >99% (E)-isomer ( I The crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at 22.0 ± 0.2 degrees 2-theta.

[0168] In some embodiments, the compound ( I Crystalline form B of ) is characterized by X-ray powder diffraction patterns having signals at 2-theta values ​​of 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least 10 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least nine 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, the compound ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, the compound ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at at least two 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, the compound ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2.

[0169] In some embodiments, a compound containing >99% (E)-isomers ( ICrystalline form B of ) is characterized by X-ray powder diffraction patterns having signals at 2-theta values ​​of 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, a compound containing >99% of (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least 10 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, a compound comprising >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least nine 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, a compound comprising >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, a compound comprising >99% (E)-isomer ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, a compound comprising >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, a compound comprising >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, a compound comprising >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, a compound comprising >99% (E)-isomer ( ICrystalline form B of ) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, a compound comprising >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at at least two 2-theta values ​​selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2. In some embodiments, a compound comprising >99% (E)-isomer ( I Crystalline form B of ) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected from 4.2 ± 0.2, 5.1 ± 0.2, 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 21.2 ± 0.2, and 22.0 ± 0.2.

[0170] In some embodiments, the compound ( I Crystalline form B of ) features an X-ray powder diffraction pattern substantially similar to that of FIG. 4b. In some embodiments, a compound ( comprising >99% (E)-isomer) I The crystalline form B of ) features an X-ray powder diffraction pattern substantially similar to that of Fig. 4b.

[0171] In some embodiments, the present invention relates to a compound prepared by a method comprising the following ( IProvides a crystalline form B of ) by adding ethyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile to form a solution. In some embodiments, the method further comprises the step of seeding sodium chloride into the solution and stirring to obtain a suspension. In some embodiments, the method further comprises the step of isolating the crystalline form B by filtration of the suspension.

[0172] In some embodiments, the present invention comprises a compound ( I The present invention provides a method for preparing a crystalline form B of ): the step of dissolving amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile in ethyl acetate to form a solution. In some embodiments, the method comprises a compound ( I Crystalline form A and compound ( I The method further includes the step of obtaining a slurry by seeding a mixture of crystalline forms A and B of ) I It further includes the step of obtaining the crystalline form B of ).

[0173] In some embodiments, the present invention relates to a compound prepared by a method comprising the following ( I ) provides a crystalline form B of: a step of dissolving amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile in ethyl acetate to form a solution. In some embodiments, the method comprises a compound ( ICrystalline form A and compound ( I The method further includes the step of obtaining a slurry by seeding a mixture of crystalline forms A and B of ) I It further includes the step of obtaining the crystalline form B of ).

[0174] In some embodiments, the present method comprises a compound comprising 95% to 99% (E)-isomers prepared by a method comprising the following: I Provides a crystalline form B of ): a step of adding ethyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile to form a solution. In some embodiments, the method further comprises the step of seeding sodium chloride into the solution and stirring to obtain a suspension. In some embodiments, the method further comprises the step of isolating crystalline form B containing 95% to 99% of the (E)-isomer by filtration of the suspension.

[0175] In some embodiments, the present invention comprises a compound comprising 95% to 99% (E)-isomers ( I The present invention provides a method for preparing a crystalline form B of ): the step of dissolving amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile in ethyl acetate to form a solution. In some embodiments, the method comprises a compound ( I Crystalline form A and compound ( IThe method further comprises the step of obtaining a slurry by seeding a mixture of crystalline forms A and B of ) I It further includes the step of obtaining the crystalline form B of ).

[0176] In some embodiments, the present method comprises a compound comprising 95% to 99% (E)-isomers prepared by a method comprising the following: I ) provides a crystalline form B of: a step of dissolving amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile in ethyl acetate to form a solution. In some embodiments, the method comprises a compound ( I Crystalline form A and compound ( I The method further comprises the step of obtaining a slurry by seeding a mixture of crystalline forms A and B of ) I It further includes the step of obtaining the crystalline form B of ).

[0177] In some embodiments, the present invention comprises a compound ( I Provides a method for preparing the crystalline form B of ): compound ( I A step of dissolving the crystalline form of C of ) in ethanol to form a solution or slurry. In some embodiments, the method comprises the solution or slurry of the compound ( I The method further includes the step of seeding the crystalline form B of ). In some embodiments, the method further includes the step of obtaining a precipitate by filtration. In some embodiments, the method dries the precipitate under vacuum to obtain the compound ( IThe method further includes the step of obtaining a crystalline form B of ). In some embodiments, drying the precipitate under vacuum includes applying heat.

[0178] In some embodiments, crystalline form C is dissolved at about 15°C. In some embodiments, the solution or slurry seeded with crystalline form B is stirred at room temperature for a predetermined period. In some embodiments, the period is about 48 hours.

[0179] In some embodiments, the present invention comprises a compound comprising >99% (E)-isomers ( I Provides a method for preparing the crystalline form B of ): compound ( I A step of dissolving the crystalline form of C of ) in ethanol to form a solution or slurry. In some embodiments, the method comprises the solution or slurry of the compound ( I The method further comprises the step of seeding the crystalline form B of ). In some embodiments, the method further comprises the step of obtaining a precipitate by filtration. In some embodiments, the method dries the precipitate under vacuum to obtain a compound (containing >99% of (E)-isomers) I The method further includes the step of obtaining a crystalline form B of ). In some embodiments, drying the precipitate under vacuum includes applying heat.

[0180] In some embodiments, crystalline form C is dissolved at about 15°C. In some embodiments, the solution or slurry seeded with crystalline form B is stirred at room temperature for a predetermined period. In some embodiments, the period is about 48 hours.

[0181] Compound ( I Crystalline form of ) C

[0182] In some embodiments, the present invention relates to a compound ( I Provides the crystalline form C of ):

[0183] ( I )

[0184] Here, *C is the stereochemical center.

[0185] Crystalline form C is a compound ( I It is an acetonitrile solvate of ).

[0186] Figure 7 shows the compound ( I This shows the X-ray powder diffraction pattern of the crystalline form of C.

[0187] Figure 8 shows the compound ( I Shows the DSC thermogram of the crystalline form C of ). In some embodiments, compound ( I The crystalline form C of ) is characterized by a DSC thermogram having a peak endothermic (melting temperature) at about 118.5 °C to about 119 °C. In some embodiments, the compound ( I The crystalline form C of ) is characterized by a DSC thermogram indicating the initiation of melting / decomposition at about 115.6 °C to about 116.0 °C. In some embodiments, the compound ( I The crystalline form C of ) is characterized by a DSC thermogram indicating melting initiation at approximately 115.6 ℃ to approximately 116.0 ℃.

[0188] Figure 8 also shows the compound ( I TGA thermal curves for the crystalline form C of ) are shown. In some embodiments, the crystalline form C is characterized by a mass loss of less than 5% at 25°C to 150°C.

[0189] The DSC thermograms in Fig. 8 were obtained using a TA Instruments Q100 or Q2000 differential scanning calorimeter equipped with a refrigerated cooling system and an autosampler under a 40 mL / min N2 purge. The DSC thermograms of the screening samples were obtained in a crimped Al pan at 15 °C / min. The TGA thermograms were obtained using a TA Instruments Q50 thermogravimetric analyzer under a 40 mL / min N2 purge in a Pt or Al pan. Unless otherwise noted, the TGA thermograms of the screening samples were obtained at 15 °C / min.

[0190] Fig. 9 shows a compound ( I Different DSC thermograms of the crystalline form C of ) are shown. The conditions for DSC were the same as for FIG. 8, except that the temperature scan rate was 10 °C / min. In some embodiments, the compound ( I The crystalline form C of ) is characterized by a DSC thermogram having a peak endothermic (melting temperature) at about 120.5 °C to about 121 °C. In some embodiments, the compound ( I The crystalline form C of ) is characterized by a DSC thermogram indicating the initiation of melting / decomposition at approximately 118.0 ℃ to approximately 118.5 ℃.

[0191] Fig. 9 also shows the compound ( I TGA thermal curves for the crystalline form C of ) are shown. The TGA conditions were the same as for FIG. 8, except that the temperature scan rate was 10 °C / min. In some embodiments, the crystalline form C is characterized by a mass loss of less than 5 wt% at 25 °C to 145 °C. In some embodiments, the mass loss is due to the removal of acetonitrile.

[0192] In some embodiments, for example, as shown in FIG. 10, which is a TG-FTIR thermogram of the crystalline form C, the compound ( IForm C of ) decomposes at higher temperatures (temperatures higher than 250 °C). FIG. 10 also indicates that there is a mass loss of 5.5% at 100 °C to 200 °C. In some embodiments, the mass loss is attributed to the loss of acetonitrile.

[0193] In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having a signal substantially similar to those mentioned in Table 3.

[0194] [Table 3]

[0195]

[0196]

[0197] In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having a signal at 2-theta of 9.8 ± 0.2. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having a signal at 10.2 ± 0.2 θ. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having a signal at 15.6 ± 0.2 2-theta. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having a signal at 16.6 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having a signal at 18.6 ± 0.2 degrees 2-theta. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having a signal at 18.9 ± 0.2 degrees 2-theta. In some embodiments, the compound ( IThe crystalline form C of ) is characterized by an X-ray powder diffraction pattern having a signal at 19.6 ± 0.2 2-theta. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having a signal at 21.6 ± 0.2 degrees 2-theta.

[0198] In some embodiments, the compound ( I The crystalline form C of ) is characterized by X-ray powder diffraction patterns having signals at 2-theta values ​​of 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, the compound ( IThe crystalline form C of ) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having a signal at at least two 2-theta values ​​selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. In some embodiments, the compound ( I The crystalline form C of ) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected from 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2.

[0199] In some embodiments, the compound ( I The crystalline form C of ) features an X-ray powder diffraction pattern substantially similar to that of Fig. 7.

[0200] In some embodiments, the compound ( I The crystalline form C of ) features a single crystal structure substantially similar to that of FIG. 11.

[0201] In some embodiments, the compound (I The crystalline form C of ) is characterized by the P-1 space group.

[0202] In some embodiments, the compound ( I The crystalline form C of ) is characterized by the P-1 space group and the following unit cell dimensions:

[0203] a = 10.67 Å α = 93.65°

[0204] b = 12.77 Å β= 104.40°

[0205] c = 14.53 Å γ = 105.48°.

[0206] In some embodiments, the compound ( I The crystalline form C of ) is characterized by the P-1 space group and the following unit cell dimensions:

[0207] a = 10.674 Å α = 93.654°

[0208] b = 12.768 Å β= 104.400°

[0209] c = 14.529 Å γ = 105.476°.

[0210] In some embodiments, the compound ( I The crystalline form C of ) is characterized by the P-1 space group and the following unit cell dimensions:

[0211] a = 10.6741 Å α = 93.6543°

[0212] b = 12.7684 Å β= 104.4003°

[0213] c = 14.5287 Å γ = 105.4764°.

[0214] In some embodiments, the compound ( I The crystalline form C of ) is characterized by the P-1 space group and the following unit cell dimensions:

[0215] a = 10.67411 Å α = 93.6543°

[0216] b = 12.76842 Å β= 104.4003°

[0217] c = 14.52872 Å γ = 105.4764°.

[0218] In some embodiments, the compound ( I The crystalline form C of ) is characterized by the P-1 space group and the following unit cell dimensions:

[0219] a = 10.674113 Å α = 93.6543°

[0220] b = 12.768416 Å β= 104.4003°

[0221] c = 14.528715 Å γ = 105.4764°.

[0222] In some embodiments, the compound ( I The crystalline form C of ) is characterized by the following unit cell dimensions at the P-1 space group and 200(2) K:

[0223] a = 10.67 Å α = 93.65°

[0224] b = 12.77 Å β= 104.40°

[0225] c = 14.53 Å γ = 105.48°.

[0226] In some embodiments, the compound ( I The crystalline form C of ) is characterized by the following unit cell dimensions at the P-1 space group and 200(2) K:

[0227] a = 10.674 Å α = 93.654°

[0228] b = 12.768 Å β= 104.400°

[0229] c = 14.529 Å γ = 105.476°.

[0230] In some embodiments, the compound ( I The crystalline form C of ) is characterized by the following unit cell dimensions at the P-1 space group and 200(2) K:

[0231] a = 10.6741 Å α = 93.6543°

[0232] b = 12.7684 Å β= 104.4003°

[0233] c = 14.5287 Å γ = 105.4764°.

[0234] In some embodiments, the compound ( I The crystalline form C of ) is characterized by the following unit cell dimensions at the P-1 space group and 200(2) K:

[0235] a = 10.67411 Å α = 93.6543°

[0236] b = 12.76842 Å β= 104.4003°

[0237] c = 14.52872 Å γ = 105.4764°.

[0238] In some embodiments, the compound ( I The crystalline form C of ) is characterized by the following unit cell dimensions at the P-1 space group and 200(2) K:

[0239] a = 10.674113 Å α = 93.6543°

[0240] b = 12.768416 Å β= 104.4003°

[0241] c = 14.528715 Å γ = 105.4764°.

[0242] In some embodiments, the present invention comprises a compound ( I The present invention provides a method for preparing a crystalline form C of ) by adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile to form a solution. In some embodiments, the method comprises adding the compound ( IThe method further includes the step of seeding crystalline form B of ) to form a mixture and stirring the mixture to obtain a slurry. In some embodiments, the method further includes the step of filtering the slurry to isolate crystalline form C.

[0243] In some embodiments, the present invention relates to a compound prepared by a method comprising the following ( I ) provides a crystalline form C of: a step of forming a solution by adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile. In some embodiments, the method provides a compound ( I The method further includes the step of seeding crystalline form B of ) to form a mixture and stirring the mixture to obtain a slurry. In some embodiments, the method further includes the step of filtering the slurry to isolate crystalline form C.

[0244] In some embodiments, the present invention comprises a compound ( I The present invention provides a method for preparing a crystalline form C of ) by adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile to form a solution. In some embodiments, the method comprises adding the compound ( I The method further comprises the step of seeding and stirring the crystalline form C of ) to obtain a precipitate. In some embodiments, the method further comprises the step of filtering the precipitate to isolate the crystalline form C. In some embodiments, the method dries the precipitate under vacuum to obtain a compound ( I It further includes the step of obtaining the crystalline form C of ).

[0245] In some embodiments, the present invention relates to a compound prepared by a method comprising the following ( I ) provides a crystalline form C of: a step of forming a solution by adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile. In some embodiments, the method provides a compound ( I The method further comprises the step of seeding and stirring the crystalline form C of ) to obtain a precipitate. In some embodiments, the method further comprises the step of filtering the precipitate to isolate the crystalline form C. In some embodiments, the method dries the precipitate under vacuum to obtain a compound ( I It further includes the step of obtaining the crystalline form C of ).

[0246] In some embodiments, the present invention comprises a compound ( I Provides a method for preparing the crystalline form C of ): compound ( in an acetonitrile / t-butyl methyl ether mixture I A step of stirring a mixture of crystalline forms A and B of ) and a mixture of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile. In some embodiments, the method further comprises the step of seeding crystalline form A into the mixture and optionally adding an additional amount of acetonitrile / t-butylmethyl ether mixture to obtain a suspension. In some embodiments, the suspension is a concentrated suspension. In some embodiments, the method filters the suspension to obtain the compound ( I It additionally includes a step of isolating the crystalline form C of ).

[0247] In some embodiments, the present invention relates to a compound prepared by a method comprising the following (I Provides the crystalline form C of ): compound (in an acetonitrile / t-butyl methyl ether mixture I A step of stirring a mixture of crystalline forms A and B of ) and a mixture of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile. In some embodiments, the method further comprises the step of seeding crystalline form A into the mixture and optionally adding an additional amount of acetonitrile / t-butylmethyl ether mixture to obtain a suspension. In some embodiments, the suspension is a concentrated suspension. In some embodiments, the method filters the suspension to obtain the compound ( I It additionally includes a step of isolating the crystalline form C of ).

[0248] Indications

[0249] Compounds described herein ( I The crystalline form of ) may be useful for treating pathological conditions mediated by BTK activity in mammals. In some embodiments, the compound described herein ( I The crystalline form of ) can be used to treat humans or non-humans.

[0250] Compounds described herein ( IThe crystalline form of ) is, for example, pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus erythematosus, dermatitis, alopecia areata, vitiligo, pyoderma gangrenosolus, membranous pemphigus, acquired epidermolysis bullosa, Stevens-Johnson syndrome, TEN toxic epidermal necrolysis, drug rash, alopeciatic folliculitis, palmoplantar pseudofolliculitis, leukocytoclastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, acne, mycosis fungoides, Sweet syndrome, inflammatory bowel disease, arthritis, lupus, lupus nephritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, Sjögren's syndrome, multiple sclerosis, ankylosing spondylitis, scleroderma, Wegener's granulomatosis, psoriasis, asthma, colitis, conjunctivitis, dermatitis, uveitis, eczema, diffuse large B-cell lymphoma, It may be useful for treating various conditions or diseases such as follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmocytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) giant B-cell lymphoma, non-Hodgkin lymphoma, intravascular giant B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, and lymphomatous granulomatosis.

[0251] Pemphigus is a rare B-cell-mediated autoimmune disease that causes debilitating intraepithelial vesicles and erosions on the skin and / or mucous membranes. Pemphigus occurs in approximately 0.1 to 0.5 people per 100,000 annually, with a mortality rate of 10%, generally due to treatment side effects and infections caused by damaged tissue (Scully et al., 2002; Scully et al., 1999). The characteristic intraepithelial vesicles observed in patients with pemphigus are caused by the binding of IgG autoantibodies to specific keratinocyte desmosome adhesion proteins, desmoglein 1 and 3 (Dsg1 and Dsg3), resulting in a loss of cell adhesion (Amagai M et al., 2012; Diaz LA et al., 2000). B cells play a crucial role in the production of these autoantibodies and in the mechanisms of cellular tolerance.

[0252] Immune thrombocytopenia (commonly referred to as ITP) is characterized by autoantibody-mediated platelet destruction and impaired platelet production, which leads to a bleeding predisposition and thrombocytopenia associated with morbidity and mortality. There is preliminary evidence supporting the role of BTK inhibition in patients with autoimmune cytopenia, in which consecutive episodes of severe autoimmune hemolytic anemia and ITP were interrupted following the initiation of treatment with the BTK / EGFR / ITK inhibitor ibrutinib in patients with chronic lymphocytic leukemia (CLL) (Reference [Rogers 2016, Montillo 2017]).

[0253] Pharmaceutical composition

[0254] The crystalline form described herein is useful not only as an active pharmaceutical ingredient (API) but also as a material for preparing a pharmaceutical composition suitable for administration to human subjects, which includes one or more pharmaceutically acceptable excipients. In some embodiments, such pharmaceutical compositions may be pharmaceutical products in formulations such as tablets and / or capsules, e.g., solid oral administrations.

[0255] In some embodiments, the present invention relates to a compound ( I The present invention provides a pharmaceutical composition comprising at least one crystalline form of ). In some embodiments, the present invention provides a compound ( I The present invention provides a pharmaceutical composition comprising at least one crystalline form of ) and at least one additional pharmaceutically acceptable excipient. Each excipient must be "pharmaceutically acceptable" in the sense that it is compatible with the target composition and that its component is not harmful to the patient. For example, any conventional pharmaceutically acceptable excipient, such as by causing any undesirable biological effect or interacting in a harmful manner with any other component(s) of the pharmaceutically acceptable composition, is a compound ( I Except for cases of incompatibility with ), its use is considered to fall within the scope of the present invention.

[0256] Some non-limiting examples of materials that may serve as pharmaceutically acceptable excipients include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and derivatives thereof, e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository waxes; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, e.g., propylene glycol; (11) polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, e.g., ethyl oleate and ethyl laurate; (13) agar; (14) buffers, e.g., magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) water without pyrogens; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic, compatible substances used in pharmaceutical formulations.

[0257] The literature [Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia] and the literature [Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York] (the contents of each of these are incorporated herein by reference) also disclose additional non-limiting examples of known techniques for manufacturing and using pharmaceutically acceptable excipients, as well as pharmaceutically acceptable excipients.

[0258] The pharmaceutical compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or through an implanted reservoir. As used herein, the term “parenterally” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intravertebral, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions of the present invention are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the pharmaceutical compositions of the present invention may be an aqueous or oily suspension. Such suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oil is typically used as a solvent or suspension medium.

[0259] To this end, any blended fixed oil containing synthetic mono- or diglycerides may be used. In particular, fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tween and Span, and other emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0260] The pharmaceutical compositions disclosed herein may also be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. Where an aqueous suspension is required for oral use, the active ingredient is typically combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or colorings may also be added.

[0261] Alternatively, the pharmaceutical composition disclosed herein may be administered in the form of a suppository for rectal administration. The suppository may be prepared by mixing the formulation with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, so that it melts at the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0262] In particular, where the treatment target involves areas or organs that are easily accessible by topical application, such as diseases of the eyes, skin, or lower gastrointestinal tract, the pharmaceutical compositions of the present invention may also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application to the lower gastrointestinal tract may be achieved with rectal suppository formulations or suitable enema formulations. Topical transdermal patches may also be used.

[0263] For topical application, the pharmaceutical composition may be formulated into a suitable ointment containing an active ingredient suspended or dissolved in at least one excipient. Excipients for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum jelly, white petroleum jelly, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical composition disclosed herein may be formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in at least one pharmaceutically acceptable excipient. Suitable excipients include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0264] The pharmaceutical composition of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants.

[0265] dosage

[0266] Generally, compounds ( I The crystalline form of ) will be administered at a therapeutically effective dose by any mode of administration acceptable for formulations providing similar utility. The effective dose for any specific mammal (e.g., any specific human) will depend on various factors including: the disorder being treated and the severity of the disorder; the specific pharmaceutical composition used; the age, weight, general health, sex, and diet of the mammal; and factors well known in the pharmaceutical field, such as the time of administration, route of administration, and duration of treatment. In some embodiments, the compound ( IA therapeutically effective amount of at least one crystalline form of ) is administered to mammals requiring it. The therapeutically effective amount of the crystalline form disclosed herein may be in the range of 0.01 to 500 mg per day per patient body weight of 1 kg, and may be administered as a single or multiple dose. Suitable dosage levels may be 0.01 to 250 mg / kg per day, 0.05 to 100 mg / kg per day, or 0.1 to 50 mg / kg per day. Within these ranges, in some embodiments, the dosage may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, in some embodiments, the composition may be provided in the form of tablets containing 1.0 to 1000 milligrams of an active ingredient, e.g., 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of an active ingredient.

[0267] Generally, the crystalline form of the present invention will be administered as a pharmaceutical composition by any of the following routes: oral; systemic (e.g., transdermal, intranasal, or via suppository); topical; or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. Exemplarily, the composition may take the form of a tablet, capsule, semi-solid, powder, sustained-release formulation, enteric-coated or delayed-release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0268] All publications and patents mentioned herein are incorporated by reference in their entirety, as if each individual publication or patent were specifically and individually included by reference.

[0269] A claim or description containing "or" or "and / or" among at least one member of a group is deemed satisfied where one, more than one, or all of the members of the group are present in, used therein, or associated therewith, unless conflicting or otherwise evident from the context. The present invention comprises an embodiment in which exactly one member of the group is present in, used therein, or associated therewith. The present invention comprises an embodiment in which more than one or all members of the group are present in, used therein, or associated therewith, the given product or method.

[0270] Additionally, the present invention includes all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the enumerated claims is introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in other claims dependent on the same base claim. Where elements are presented as a list (e.g., in the Markush group format), each subgroup of elements is also disclosed, and any element(s) may be removed from the group. In general, where the present invention, or an aspect of the invention, is referred to as including a specific element and / or feature, it should be understood that an embodiment of the present invention or an aspect of the present invention is made up of or essentially made up of such element and / or feature. For simplicity, such embodiments are not specifically presented herein in exactly the same way. Where a scope is given, an endpoint is included. Additionally, unless otherwise stated or is not evident from the context and the understanding of those skilled in the art, values ​​indicated by ranges may take any specific value or sub-range within the range mentioned in different embodiments of the present invention up to 1 / 10 of the unit of the lower limit of the range, unless otherwise evidently stated in the context.

[0271] A person skilled in the art will be able to recognize or identify various equivalents to specific embodiments of the invention described herein merely by ordinary experiment. Such equivalents are intended to be included in the following claims.

[0272] Examples

[0273] The following examples are intended to illustrate and do not limit the present disclosure in any way.

[0274] Analysis Method 1: Powder X-ray Diffraction

[0275] Powder X-ray diffraction can be performed using a Stoe Stadi P diffractometer equipped with a Mythen1K detector operating on Cu-Kα1 radiation. Measurements using this instrument can be performed at a tube voltage of 40 kV and a tube output of 40 mA for transmission. A curved Ge monochromator can be used for testing with Cu-Kα1 radiation. The following parameters can be set: 0.02° 2θ step size, 12 s step time, 1.5–50.5° 2θ scanning range, and 1° 2θ detector step (detector mode in step scan). For typical sample preparation, approximately 10 mg of sample is placed between two acetate foils and mounted in a Stoe transmission sample holder. The sample is rotated during measurement. All sample preparation and measurements can be performed in an ambient air atmosphere.

[0276] Analysis Method 2: Powder X-ray Diffraction (PXRD) Panalytical

[0277] The PXRD diffraction pattern is Ni-filtered Cu Ka (45 kV / 40 mA) radiation and 0.03 o Step size of 2q and X'celerator TMIt can be acquired on a PANalytical X'Pert Pro diffractometer using an RTMS (Real-time Multi-strip) detector. The configuration on the incident beam side may be as follows: a variable divergence slit (10 mm irradiation length), a 0.04 rad Soller slit, and a fixed anti-scattering slit (0.50 o ) and a 10 mm beam mask. The configuration on the diffraction beam side may be: a variable anti-scattering slit (10 mm observation length) and a 0.04 rad Soller slit. The sample is mounted flat on a background-free Si wafer.

[0278] Analysis Method 3: Differential Scanning Calorimetry (DSC)

[0279] DSC can be performed using a TA Instruments Q100 or Q2000 differential scanning calorimeter equipped with a cold cooling system and an autosampler under a 40 mL / min N2 purge. A DSC thermogram of the screening sample can be obtained at 15 °C / min in a crimped Al pan.

[0280] Analysis Method 4: Thermogravimetric Analysis (TGA)

[0281] TGA thermograms can be obtained using a TA Instruments Q50 thermogravimetric analyzer under 40 mL / min N2 purging in a Pt or Al pan. TGA thermograms of screening samples can be obtained at 15 ℃ / min.

[0282] Analysis Method 5: Thermogravimetric Analysis using IR Off-Gas Detection (TGA-IR)

[0283] TGA-IR can be performed using a TA Instruments Q5000 thermogravimetric analyzer interfaced to a Nicolet 6700 FT-IR spectrometer (Thermo Electron) equipped with an external TGA-IR module having a gas flow cell and a DTGS detector. TGA is performed in a Pt or Al pan with a 25 mL / min N2 flow and 15 o It can be performed at a heating rate of C / min. The IR spectrum is 4 cm at each time point. -1It can be collected with resolution and 32 scans.

[0284] Analysis Method 6: Fourier Transform Infrared Spectroscopy (TG-FTIR)

[0285] Thermogravimetric measurements can be performed using a Netzsch Thermo-Microbalance TG 209 coupled to a Bruker FTIR Spectrometer Vector 22 (sample pan with pinholes, N2 atmosphere, heating rate 10°C / min).

[0286] General method:

[0287] Compound ( I As part of the polymorph study on ), several crystallization experiments were performed. The experiments included various crystallization techniques such as suspension equilibrium experiments, precipitation, cooling crystallization, and vapor diffusion experiments.

[0288] Example 1: Preparation of crystalline form A of compound (I)

[0289] 98 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile was dissolved in 400 μL of isopropyl acetate at room temperature. After stirring for 1 day, a very concentrated suspension was obtained. An additional 700 μL of isopropyl acetate was added, and after stirring for 2 hours, the suspension was filtered (centrifuge unit filter, PTFE, 0.22 μm) to obtain crystalline form A.

[0290] Example 2: Preparation of crystalline form B of compound (I) containing 95% to 99% of (E)-isomer

[0291] 96 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile was dissolved in 0.3 mL of ethyl acetate. NaCl was seeded into the resulting solution and stirred at room temperature. After stirring overnight, a turbid solution was obtained and sonicated for 5 minutes. After stirring for an additional 2 days, a suspension was obtained and filtered (centrifuge unit filter, PTFE, 0.22 μm) to obtain crystalline form B.

[0292] Example 3: Alternative preparation of crystalline form B of compound (I) containing 95% to 99% of (E)-isomer

[0293] 3.64 g of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile was dissolved in ethyl acetate (EtOAc) (11 mL) at room temperature (RT), and crystalline form A (20 mg) and a mixture of crystalline forms A and B (60 mg) were seeded. Seeding was continued. The resulting slurry was stirred at RT for 3 days. Heptane (33 mL) was added dropwise (continuously), and the slurry was stirred at RT for 4 hours. The slurry was filtered and dried under vacuum at 30°C for 16 hours to obtain 3.5 g of crystalline form B (94% yield).

[0294] Example 4: Alternative preparation of crystalline form B of compound (I) containing >99% (E)-isomer

[0295] 430 g of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile(compound ( IForm C of )) was combined with ethanol (4.1 L) at approximately 15 °C to form a slurry. Subsequently, seed crystals of Form B were added (up to approximately 5 wt%), and the slurry was stirred for approximately 2 days. The slurry was filtered and dried under vacuum using heat to obtain the compound ( I Approximately 300 g of crystalline form B of ) was obtained (74% yield).

[0296] Example 5: Preparation of crystalline form C of compound (I)

[0297] 100 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile was combined with acetonitrile (MeCN) (0.5 mL; 5 vol). Compound ( I Crystalline form B of ) was seeded and stirred at room temperature for 48 hours. At approximately 48 hours, a dark white free-flowing slurry was obtained and determined to be crystalline form C. Estimated yield: >50%.

[0298] Example 6: Alternative preparation of crystalline form C of compound (I) 1

[0299] 61.2 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile, and a mixture of 49.8 mg of crystalline forms A and B were suspended at room temperature in 400 μL of acetonitrile / t-butyl methyl ether (TBME) (1:1) mixture. After stirring for 10 minutes, crystalline form A was seeded into the suspension. After stirring overnight at room temperature, an additional 400 μL of acetonitrile / TBME (1:1) mixture was added. After stirring at room temperature for 5 days, a very concentrated suspension was obtained, and 600 μL of acetonitrile / TBME (1:1) mixture was added. After stirring for a total of 2 weeks, the suspension was filtered (centrifuge unit filter, PTFE, 0.22 μm), and the recovered solid was dried in air for approximately 1 hour to provide a crystalline form C.

[0300] Example 7: Alternative preparation of crystalline form C of compound (I) 2

[0301] 9.3 g of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile was combined with MeCN (93 mL; 10 vol). Seed crystals (35 mg) of crystalline form C were seeded into the solution and stirred at room temperature for 72 hours. Precipitation was observed after 2 hours. The solid was separated by filtration and dried under vacuum at 30°C for 1 hour to obtain crystalline form C. Yield: 76%.

[0302] Example 8: Alternative preparation of crystalline form C of compound (I) 3

[0303] 100 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile was combined with MeCN / MTBE (1:1; 1.4 mL). Seed crystals of crystalline form B were seeded into the solution. The seeds dissolved. Subsequently, a mixture of seed crystals of crystalline forms A and B was seeded into the solution and stirred for 48 hours. No significant precipitation was observed. Subsequently, seed crystals of crystalline form C were seeded into the solution. Slight thickening was observed. The solution was stirred for 5 days, and the precipitate obtained by filtration was crystalline form C. Yield: 42%.

[0304] Example 9: Single-crystal X-ray diffraction

[0305] Compound in a small bottle ( I )(10.2 mg) was dissolved in an internal solvent (acetonitrile), and then a small vial was placed in a larger vial containing an external solvent (isopropyl ether) and left at 4°C for 15 days to grow a single crystal. Single-crystal X-ray diffraction data were collected on a Bruker D8 Venture DUO diffractometer using graphite-monochromatic MoKα (λ = 0.71073 Å) radiation. The crystal was mounted on a MiTeGen MicroMount and collected at 200°C (2) K using an Oxford Cryosystems 800 cryosystem. Data were collected using omega and pi scans and corrected for Lorentz and polarization effects using the APEX3 software suite and WinGX publishing routines (Farrugia, 2005). All images were prepared using Ortep-3 for Windows.

[0306] The single crystal exhibited the P-1 space group of the triclinic system. The following unit cell dimensions were measured:

[0307] a = 10.6741(13) Å α = 93.654(3)°.

[0308] b = 12.7684(16) Å β = 104.400(3)°.

[0309] c = 14.5287(15) Å γ = 105.476(4)°.

Claims

Claim 1 Compound ( I It is the crystalline form A of ): ( I Crystalline form A, characterized by an X-ray powder diffraction pattern having a signal at at least three 2-theta values ​​selected from 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2 (wherein C* is the stereochemical center). Claim 2 Crystalline form A according to claim 1, further characterized by an X-ray powder diffraction pattern as shown in FIG. 1 below: [Fig. 1] . Claim 3 Crystalline form A, further characterized in that, in claim 1, a DSC thermogram having a peak endothermic (melting temperature) at 146 ℃ ± 5% to 147 ℃ ± 5%. Claim 4 Crystalline form A according to claim 1, further characterized by a DSC thermogram indicating melting initiation at 140.6 ℃ ± 5% to 141.2 ℃ ± 5%. Claim 5 Crystalline form A according to claim 1, further characterized by a mass loss of less than 1.0 wt% at 25 ℃ to 200 ℃ by thermogravimetric analysis. Claim 6 Crystalline form A according to claim 1, further characterized by a water content of less than 1% when stored at 95% relative humidity (RH). Claim 7 In paragraph 1, the compound ( I Crystalline form A, of which at least 95% is an isomer of (E). Claim 8 A compound according to any one of paragraphs 1 to 7 ( I A method for preparing a crystalline form A of ) comprising the steps of: adding isopropyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile to form a solution; stirring the solution to form a precipitate; and isolating the crystalline form A by filtration. Claim 9 Compound ( I It is the crystalline form B of ): ( I Crystalline form B, characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected from )(wherein C* is the stereochemical center), 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.0 ± 0.2, and 22.9 ± 0.

2. Claim 10 In paragraph 9, the compound ( I Crystalline form B, of which at least >99% is an isomer of (E). Claim 11 In paragraph 9, the compound ( I 95% to 99% of ) is the crystalline form B, which is an isomer of (E). Claim 12 In claim 10, crystalline form B further characterized by an X-ray powder diffraction pattern as shown in FIG. 4b below: [Fig. 4b] . Claim 13 In claim 11, crystalline form B further characterized by an X-ray powder diffraction pattern as shown in FIG. 4a below: [Fig. 4a] . Claim 14 Crystalline form B, further characterized in that, in claim 10, a DSC thermogram having a peak endothermic (melting temperature) at 144 ℃ ± 5% to 146 ℃ ± 5%. Claim 15 In claim 10, crystalline form B, further characterized by a DSC thermogram indicating melting initiation at 139.3 ℃ ± 5%. Claim 16 Crystalline form B according to claim 11, further characterized by a DSC thermogram having a peak endothermic (melting temperature) at 141 ℃ ± 5% to 142 ℃ ± 5%. Claim 17 Crystalline form B according to claim 11, further characterized by a DSC thermogram indicating melting initiation at 131.8 ℃ ± 5% to 132.4 ℃ ± 5%. Claim 18 In claim 9, crystalline form B, further characterized by a water content of less than 1.3% when stored at 95% relative humidity (RH). Claim 19 A compound according to any one of paragraphs 9 through 18 ( I A method for preparing crystalline form B of ) comprising: a step of adding ethyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile to form a solution; a step of seeding the solution with sodium chloride and stirring the solution to obtain a suspension; and a step of isolating crystalline form B by filtration of the suspension. Claim 20 Compound ( I It is the crystalline form of ) C: ( I Crystalline form C, characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected from )(wherein C* is the stereochemical center), 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.

2. Claim 21 In claim 20, crystalline form C, further characterized by an X-ray powder diffraction pattern as shown in Fig. 7 below: [Fig. 7] . Claim 22 In claim 20, further characterized by a DSC thermogram having a peak endothermic (melting temperature) at 118.5 ℃ ± 5% to 119 ℃ ± 5%, wherein the DSC scanning rate is 15 Crystalline form C, with a temperature of ℃ / min. Claim 23 In claim 20, the crystalline form C is further characterized by a DSC thermogram indicating melting initiation at 115.6 ℃ ± 5% to 116 ℃ ± 5%, wherein the DSC scanning rate is 15 ℃ / min. Claim 24 In claim 20, the crystalline form C is further characterized by a DSC thermogram having a peak endothermic (melting temperature) at 120.5 ℃ ± 5% to 121 ℃ ± 5%, wherein the DSC scanning rate is 10 ℃ / min. Claim 25 In claim 20, the crystalline form C is further characterized by a DSC thermogram indicating melting initiation at 118 ℃ ± 5% to 118.5 ℃ ± 5%, wherein the DSC scanning rate is 10 ℃ / min. Claim 26 In paragraph 20, the compound ( I At least 95% of ) is the crystalline form C, which is an (E) isomer. Claim 27 In paragraph 20, a crystalline form C further characterized by the P-1 space group. Claim 28 In paragraph 20, the crystalline form C:a = 10.6741 Å α = 93.654°b = 12.7684 Å β= 104.400°c = 14.5287 Å γ = 105.476°, further characterized by the following unit cell dimensions at 200(2) K. Claim 29 A compound according to any one of paragraphs 9 through 18 ( I A method for preparing crystalline form B of ) and the step of adding ethanol to crystalline form C of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile defined in any one of claims 20 to 28 to form a solution or slurry; the solution or slurry of the compound ( I A step of seeding with a seed crystal of form B of ); and compound by filtration ( I A method comprising the step of isolating crystalline form B of ). Claim 30 A compound according to any one of paragraphs 20 through 28 ( I A method for preparing a crystalline form C of ) and: a step of adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pent-2-ennitrile to form a solution; and the solution of a compound defined in any one of claims 9 to 18 ( I A method comprising the steps of: seeding with crystalline form B of ) to form a mixture and stirring the mixture to obtain a slurry; and filtering the slurry to isolate crystalline form C. Claim 31 A compound selected from the crystalline form of any one of paragraphs 1 to 7, 9 to 18 and 20 to 28 ( I At least one crystalline form of ); and comprising at least one pharmaceutically acceptable excipient, pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, alopecia areata, vitiligo, pyoderma gangrenosolitis, membranous pemphigus, acquired epidermolysis bullosa, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug rash, alopeciatic folliculitis, palmoplantar pseudofolliculitis, leukocytoclastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, acne, mycosis fungoides, Sweet syndrome, inflammatory bowel disease, arthritis, lupus, lupus nephritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, Sjögren's syndrome, multiple sclerosis, ankylosing spondylitis, scleroderma, Wegener's granulomatosis, psoriasis, asthma, colitis, conjunctivitis, uveitis, eczema, diffuse large B-cell lymphoma, A pharmaceutical composition for administering to a human subject for the treatment of at least one of follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmocytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) giant B-cell lymphoma, non-Hodgkin lymphoma, intravascular giant B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, and lymphomatous granulomatosis. Claim 32 In paragraph 31, the pharmaceutical composition is in the form of a solid oral composition. Claim 33 In paragraph 32, the pharmaceutical composition is in the form of a tablet or a capsule. Claim 34 A pharmaceutical composition for inhibiting Bruton's tyrosine kinase (BTK) in mammals requiring inhibition of said BTK, comprising at least one crystalline form selected from the crystalline forms of any one of claims 1 to 7, 9 to 18, and 20 to 28, wherein the mammal has pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, alopecia areata, vitiligo, gangrenous pyoderma, membranous pemphigus, acquired epidermolysis bullosa, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug rash, alopeciatic folliculitis, psoriatic pseudofolliculitis, leukocytoclytic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, acne, mycosis fungoides, Sweet syndrome, inflammatory bowel disease, arthritis, lupus, A pharmaceutical composition having at least one of lupus nephritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, Sjögren's syndrome, multiple sclerosis, ankylosing spondylitis, scleroderma, Wegener's granulomatosis, psoriasis, asthma, colitis, conjunctivitis, uveitis, eczema, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmocytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, non-Hodgkin lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, and lymphomatous granulomatosis. Claim 35 A pharmaceutical composition for treating a disease mediated by Bruton's tyrosine kinase (BTK) in mammals requiring treatment of said disease, comprising at least one crystalline form selected from the crystalline forms of any one of claims 1 to 7, 9 to 18, and 20 to 28, wherein the disease is pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, alopecia areata, vitiligo, pyoderma gangrenosolitis, pemphigus membranosus, acquired epidermolysis bullosa, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug rash, alopeciatic folliculitis, psoriatic pseudofolliculitis, leukocytoclytic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, acne, mycosis fungoides, Sweet syndrome, inflammatory bowel disease, arthritis, lupus, lupus nephritis, rheumatoid arthritis, A pharmaceutical composition selected from psoriatic arthritis, juvenile arthritis, Sjögren's syndrome, multiple sclerosis, ankylosing spondylitis, scleroderma, Wegener's granulomatosis, psoriasis, asthma, colitis, conjunctivitis, uveitis, eczema, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmocytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, non-Hodgkin lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, and lymphomatous granulomatosis. Claim 36 A pharmaceutical composition for treating at least one of the following diseases in mammals requiring treatment: pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, asthma, and dermatitis, comprising at least one crystalline form selected from the crystalline forms of any one of claims 1 to 7, 9 to 18, and 20 to 28. Claim 37 In paragraph 36, a pharmaceutical composition in which the mammal is a human. Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete

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