Crystalline forms of 2 - [3 - [4-amino-3 - (2-fluoro-4-phenoxy-phenyl) - 1h - pyrazolor3, 4-d] pyrimidin-1-yl] piperidine-1-carbonyl] - 4-methyl-4 - [4 - (oxetan-3-yl) piperazin-1-yl] pent-2-enenitrile

Abstract

Provided are novel solid forms, including novel crystalline forms thereof, which are useful for treating disorders and conditions mediated by BTK activity.SOLUTION: (I): wherein C * is a stereochemical center; characterized by an X-ray powder diffractogram 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, 22.0 ± 0.2, and 22.9 ± 0.2.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Disclosed herein are crystalline forms of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (Compound (I)), methods of using the same, and methods for making Compound (I), including its various crystalline forms. The crystalline forms of Compound (I) are inhibitors of Bruton's tyrosine kinase (BTK). The enzyme BTK is a member of the Tec family of non-receptor tyrosine kinases. [Background technology]

[0003] BTK is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages. BTK plays a role in B cell development and activation and is involved in numerous signaling pathways across a wide range of immune-mediated diseases. BTK activity has been implicated in the pathogenesis of several disorders and conditions, such as B cell-related hematologic cancers (e.g., non-Hodgkin's 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 in treating disorders and conditions mediated by BTK activity. Compound (I) is disclosed in Example 31 of Patent Document 1 and has the following structure: [ka] (In the formula, *C is a stereochemical center.) An alternative procedure for preparing compound (I) is disclosed in Example 1 of WO 02 / 04799.

[0005] Solid forms (e.g., crystalline forms) of biologically active compounds such as Compound (I) are of interest to the pharmaceutical industry, and solid forms with particular physical, chemical, or pharmaceutical properties, such as solubility, dissociation, true density, dissolution, melting point, morphology, compaction behavior, particle size, flowability, or solid-state stability, may be desirable or required in pharmaceutical development. Crystalline forms arise when the same composition of matter crystallizes in different lattice arrangements, resulting in different thermodynamic properties and stability specific to each crystalline form. Each unique crystalline form is known as a "polymorph." do.

[0006] While polymorphs of a given substance have the same chemical composition, they may differ from one another with respect to at least one physical, chemical, and / or pharmaceutical property, such as solubility, dissociation, true density, dissolution, melting point, crystal habit or morphology, compaction behavior, particle size, flowability, and / or solid-state stability. The solid-state form of a biologically active compound often determines its ease of manufacture, ease of isolation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in vivo.

[0007] It is not yet possible to predict the possible solid forms (e.g., crystalline forms) of a compound, whether any such forms will be suitable for commercial use in pharmaceutical compositions, or which form or forms will exhibit desired properties. Because different solid forms (e.g., crystalline forms) have different properties, reproducible methods for producing substantially pure solid forms are also desirable for biologically active compounds intended for use as pharmaceuticals. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO2014 / 039899 issue [Patent Document 2] WO2015 / 127310 Summary of the Invention [Problem to be solved by the invention]

[0009] Thus, there is a need for novel solid forms, including novel crystalline forms thereof, of Compound (I), e.g., Compound (I), that are useful for treating disorders and conditions mediated by BTK activity, as well as reproducible and scalable methods of making the same. [Means for solving the problem]

[0010] Disclosed herein are novel crystalline forms of Compound (I), compositions comprising the same, and methods of using and making the same. In some embodiments, the novel crystalline forms disclosed herein have properties that make them useful for large-scale production, 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.

[0011] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising a pharmaceutically acceptable excipient; and at least one crystalline form selected from crystalline forms of Compound (I). In some embodiments, the at least one crystalline form is crystalline form A of Compound (I). In some embodiments, the at least one crystalline form is crystalline form B of Compound (I). In some embodiments, the at least one crystalline form is crystalline form C of Compound (I).

[0012] Some embodiments of the present disclosure relate to methods of inhibiting BTK in a mammal by administering to the mammal in need thereof a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of Compound (I). In some embodiments, the at least one crystalline form is crystalline Form A of Compound (I). In some embodiments, the at least one crystalline form is crystalline Form B of Compound (I). In some embodiments, the at least one crystalline form is crystalline Form C of Compound (I).

[0013] In some embodiments, the mammal in need of BTK inhibition is suffering from a BTK-mediated disease, such as pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus, cutaneous lupus erythematosus, or the like. rash, dermatitis, alopecia areata, vitiligo vulgaris, pyoderma gangrenosum, mucous membrane pemphigoid, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, TEN (toxic epidermal necrolysis), drug eruption, folliculitis barbae, pseudofolliculitis barbae, leucoclastic vasculitis, hidradenitis suppurativa, palmar and plantar pustulosis pustulosis), lichenoid dermatitis, acne, mycosis fungoides, Sweet's syndrome, inflammatory bowel disease, arthritis, lupus, lupus nephritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, Sjogren's syndrome, multiple sclerosis, ankylosing spondylitis, scleroderma, Wegener's granulomatosis, psoriasis, asthma, colitis, conjunctivitis, dermatitis, uveitis, eczema, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell lymphoma Selected from prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's 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's lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, and lymphomatoid granulomatosis.

[0014] In some embodiments, the BTK-mediated disease is pemphigus vulgaris. In some embodiments, the BTK-mediated disease is pemphigus foliaceus. In some embodiments, the BTK-mediated disease is immune thrombocytopenia. In some embodiments, the BTK-mediated disease is lupus nephritis.

[0015] In some embodiments, the mammal in need of BTK inhibition is a human. In some embodiments, the mammal in need of BTK inhibition is a dog.

[0016] Also disclosed herein are methods for preparing at least one crystalline form selected from the crystalline forms of Compound (I). Some embodiments of the present disclosure are directed to the methods, wherein the at least one crystalline form is crystalline form A of Compound (I). Some embodiments of the present disclosure are directed to the methods, wherein the at least one crystalline form is crystalline form B of Compound (I). Some embodiments of the present disclosure are directed to the methods, wherein the at least one crystalline form is crystalline form C of Compound (I). [Brief explanation of the drawings]

[0017] [Figure 1] 1 shows the X-ray powder diffraction pattern for crystalline Form A of Compound (I), herein referred to as crystalline Form A, with angle 2θ (2 theta) on the X-axis and relative intensity on the Y-axis. [Figure 2] 1 shows a differential scanning calorimetry (DSC) thermogram for crystalline Form A of Compound (I). [Figure 3] 1 shows the thermogravimetry coupled to Fourier transform infrared spectroscopy (TG-FTIR) thermal curve for crystalline form A of Compound (I). [Figure 4A]1 shows the X-ray powder diffraction pattern for crystalline form B of Compound (I), herein referred to as crystalline form B, containing 95%-99% of the (E) isomer, with angle 2θ (2 theta) on the X-axis and relative intensity on the Y-axis. [Figure 4B] 1 shows the X-ray powder diffraction pattern for crystalline form B of Compound (I), which contains over 99% of the (E) isomer, with angle 2θ (2 theta) on the X-axis and relative intensity on the Y-axis. [Figure 5A] FIG. 1 shows a differential scanning calorimetry (DSC) thermogram for crystalline form B of Compound (I), which contains 95%-99% of the (E) isomer. [Figure 5B] 1 shows a differential scanning calorimetry (DSC) thermogram for crystalline Form B of Compound (I), which contains greater than 99% of the (E) isomer. [Figure 6A] FIG. 1 shows the thermogravimetric analysis-Fourier transform infrared spectroscopy (TG-FTIR) thermal curve for crystalline form B of Compound (I), which contains 95%-99% of the (E) isomer. [Figure 6B] 1 shows the thermogravimetric analysis-Fourier transform infrared spectroscopy (TG-FTIR) thermal curve for crystalline form B of Compound (I), which contains more than 99% of the (E) isomer. [Figure 7] 1 shows the X-ray powder diffraction pattern for crystalline Form C of Compound (I), herein referred to as crystalline Form C, with angle 2θ (2 theta) on the X-axis and relative intensity on the Y-axis. [Figure 8] 1 shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) heat curve for crystalline form C, with a scan rate of 15° C. / min. [Figure 9] 1 shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) heat curve for crystalline form C, with a scan rate of 10° C. / min. [Figure 10] 1 shows the thermogravimetry-Fourier transform infrared spectroscopy (TG-FTIR) thermal curve for crystalline form C. [Figure 11] 1 shows the single crystal structure for crystalline form C. DETAILED DESCRIPTION OF THE INVENTION

[0018] Definition: As used herein, "a" or "an" attached to an entity refers to one or more of that entity; for example, "a compound" refers to one or more compounds, or at least one compound, unless otherwise stated. Thus, the terms "a" or "an," "one or more," and "at least one" are used interchangeably herein.

[0019] As used herein, the term "about" means approximately, in the region of, roughly, or around. When the term "about" is used in connection with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, the term "about" is used herein to modify a numerical value by a variance of 5% above and below the stated value.

[0020] As used herein, “Compound (I)” refers to the (E) isomer, (Z) isomer, or mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, (S)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, or a mixture of the (R) and (S) enantiomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, which has the following structure: [ka] (In the formula, * C is a stereochemical center).

[0021] When compound (I) is expressed as (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, it may contain less than 1% by weight of the corresponding (S) enantiomer as an impurity. Thus, when compound (I) is expressed as a mixture of the (R) and (S) enantiomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, the amount of the (R) or (S) enantiomer in the mixture is greater than 1% by weight. Similarly, when compound (I) is expressed as the (E) isomer, it may contain less than 1% by weight of the corresponding (Z) isomer as an impurity. Thus, when compound (I) is expressed as a mixture of the (E) and (Z) isomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, the amount of the (E) or (Z) isomer in the mixture is greater than 1% by weight.

[0022] As used herein, "crystalline form [X] of Compound (I) containing [Y]% of the (E) isomer" means that [Y]% of Compound (I) in crystalline form is the (E) isomer.

[0023] Compound (I) may be referred to herein as a "drug," "active agent," "therapeutically active agent," or "API."

[0024] As used herein, "substantially pure" with respect to a geometric isomeric form refers to a compound, such as Compound (I), in which greater than 70% by weight of the compound is present as a given isomeric form. For example, the phrase "crystalline Form A of Compound (I) is a substantially pure (E) isomer of Compound (I)" refers to crystalline Form A of Compound (I) having at least 70% by weight of crystalline Form A of Compound (I) in the (E) isomeric form, and the phrase "crystalline Form A of Compound (I) is a substantially pure (Z) isomer of Compound (I)" refers to crystalline Form A of Compound (I) having at least 70% by weight of crystalline Form A of Compound (I) in the (Z) isomeric form. In some embodiments, at least 80% by weight of the crystalline form of Compound (I) is the (E) form, or at least 80% by weight of the crystalline form of Compound (I) is the (Z) form. In some embodiments, at least 85% by weight of the crystalline form of Compound (I) is the (E) form, or at least 85% by weight of the crystalline form of Compound (I) is the (Z) form. In some embodiments, at least 90% by weight of the crystalline form of Compound (I) is the (E) form, or at least 90% by weight of the crystalline form of Compound (I) is the (Z) form. In some embodiments, at least 95% by weight of the crystalline form of Compound (I) is the (E) form, or at least 95% by weight of the crystalline form of Compound (I) is the (Z) form. In some embodiments, at least 97% by weight or at least 98% by weight of the crystalline form of Compound (I) is the (E) form, or at least 97% by weight or at least 98% by weight of the crystalline form of Compound (I) is the (Z) form. In some embodiments, at least 99% by weight of the crystalline form of Compound (I) is the (E) form, or at least 99% by weight of the crystalline form of Compound (I) is the (Z) form. The relative amounts of the (E) and (Z) isomers in a solid mixture can be determined according to standard methods and techniques known in the art.

[0025] As used herein, "pharmaceutically acceptable excipient" refers to an additive or additive that is used to prepare a pharmaceutical composition. For example, pharmaceutically acceptable excipients include carriers and excipients that are generally regarded as safe and acceptable for pharmaceutical use in mammals.

[0026] As used herein, the terms "polymorph," "crystal form," "crystalline form," and "form" refer interchangeably to a solid having a particular molecular packing arrangement in a crystal lattice. Crystalline forms can be identified and distinguished from one another 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 sorption (DVS), and / or thermogravimetric analysis (TGA). Thus, as used herein, the term "crystalline form [X] of Compound (I)" 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 sorption (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms of the present disclosure are characterized by an X-ray powder diffraction pattern having at least one signal at at least one designated two-theta value (°2θ).

[0027] As used herein, a "therapeutically effective amount" of a compound disclosed herein refers to an amount of a compound that elicits a biological or medical response in a subject. The therapeutically effective amount depends on the purpose of the treatment and can be ascertained by one skilled in the art (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0028] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0029] As used herein, the terms "treat," "treating," or "treatment," when used in reference to a disorder or condition, include any effect that results in improvement of the disorder or condition, e.g., alleviation, reduction, modulation, amelioration, or elimination. Improvement or reduction in the severity of any symptom of a disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0030] As used herein, "mammal" refers to domestic animals (e.g., dogs, cats, and horses) as well as humans. In some embodiments, the mammal is a human. In some embodiments, the mammal is a dog.

[0031] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0032] As used herein, the term "TGA" refers to the analytical method of thermogravimetric (also called thermogravimetric) analysis.

[0033] As used herein, the term "TG-FTIR" refers to the analytical method of thermogravimetry-Fourier transform infrared spectroscopy.

[0034] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in either transmission or reflection configuration using a diffractometer.

[0035] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," and "XRPD pattern" refer to an experimentally obtained pattern depicting signal position (abscissa) versus signal intensity (ordinate). For a crystalline material, an X-ray powder diffractogram can include at least one signal, each identified by its angle value measured in degrees 2θ (°2θ) shown on the abscissa of the X-ray powder diffractogram, which can be expressed as "a signal at ⋅⋅°2θ," "a signal at [one] 2θ value of ⋅⋅," and / or "a signal at at least 2θ values ​​selected from ⋅⋅."

[0036] As used herein, the term "X-ray powder diffractogram having signals at 2-theta values ​​of ⋅⋅⋅" refers to an XRPD pattern (°2θ) measured in an X-ray powder diffraction experiment and containing the positions of the observed X-ray reflections.

[0037] As used herein, the term "signal" refers to a point in an XRPD pattern where the intensity, measured in counts, is a maximum. Those skilled in the art will recognize that at least one signal in an XRPD pattern may overlap and may not be apparent to the naked eye, for example. Those skilled in the art will recognize that several art-recognized methods are capable of and suitable for determining whether a signal is present in a pattern, such as Rietveld refinement.

[0038] As used herein, the terms "signal at . . . degrees 2-theta," "signal at [one] 2-theta value [ ] of . . . .," and "signal at at least 2-theta values ​​selected from . ... By way of example, non-limiting factors that can affect relative signal strength include sample thickness and preferred orientation (eg, crystalline grains are not randomly distributed).

[0039] As used herein, an X-ray powder diffractogram is "substantially similar to that of a [particular] diffractogram" if at least 90%, e.g., at least 95%, at least 98%, or at least 99% of the signals in the two diffractograms are the same ±0.2°2θ. In determining "substantially similar," one skilled in the art will understand that variability in intensity and / or signal position may exist in XRPD diffractograms even for the same crystalline form. Thus, one skilled in the art will understand that signal maxima (referred to herein as angles 2θ (°2θ)) in an XRPD diffractogram generally mean values ​​recorded ±0.2°2θ, an art-recognized variability as discussed above.

[0040] As mentioned above, described herein are novel crystalline forms of Compound (I). These novel crystalline forms may be inhibitors of BTK. BTK inhibitors are useful for treating diseases mediated by BTK, such as pemphigus vulgaris, pemphigus foliaceus, and immune thrombocytopenia.

[0041] Embodiments: Non-limiting embodiments of the present disclosure include:

[0042] 1. Crystalline Form A of Compound (I): [ka] (In the formula, C * is a stereochemical center). 2. Crystalline form A according to embodiment 1, 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. 3. Crystalline form A according to embodiment 1 or 2, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 1. 4. Crystalline form A according to any one of embodiments 1 to 3, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 146°C to about 147°C. 5. Crystalline form A according to any one of embodiments 1 to 4, characterized by a DSC thermogram showing an onset of melting at about 140.6°C to about 141.2°C. 6. Crystalline form A according to any one of embodiments 1 to 5, characterized by a mass loss of less than 1.0 wt.% between 25°C and 200°C by thermogravimetric analysis. 7. Crystalline form A according to any one of embodiments 1 to 6, characterized by a water content of less than 1% upon storage at 95% relative humidity (RH). 8. Crystalline form A according to any one of embodiments 1 to 7, wherein at least 95% of compound (I) is the (E) isomer. 9. adding isopropyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution; stirring the solution to form a precipitate; and Isolating crystalline form A by filtration 2. Crystalline Form A of Compound (I), prepared by a process comprising:

[0043] 10. Crystalline Form B of Compound (I): [ka] (In the formula, C * is a stereochemical center). 11. Crystalline form B according to embodiment 10, 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, 22.0±0.2, and 22.9±0.2. 12. Crystalline form B according to embodiment 10 or 11, wherein at least 99% of compound (I) is the (E) isomer. 13. Crystalline form B according to embodiment 10 or 11, wherein 95% to 99% of compound (I) is the (E) isomer. 14. Crystalline form B according to any one of embodiments 10 to 12, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4B. 15. Crystalline form B according to any one of embodiments 10, 11, or 13, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4A. 16. Crystalline form B of any one of embodiments 10-12, or 14, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 144°C to about 146°C. 17. Crystalline form B of any one of embodiments 10-12, 14, or 16, characterized by a DSC thermogram showing an onset of melting at about 139.3°C. 18. Crystalline form B of any one of embodiments 10, 11, 13, or 15, characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 141°C to about 142°C. 19. Crystalline form B of any one of embodiments 10, 11, 13, 15, or 18, characterized by a DSC thermogram showing an onset of melting at about 131.8°C to about 132.4°C. 20. Crystalline form B according to any one of embodiments 10 to 19, characterized by a water content of less than 1.3% upon storage at 95% relative humidity (RH). 21. Adding ethyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution; Seed the solution with sodium chloride and stir the solution to obtain a suspension; Isolating crystalline form B by filtration of the suspension Crystalline form B of compound (I), produced by a process comprising: 22. Adding ethanol to (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile Form C to form a solution or slurry; seeding the solution or slurry with Form B of Compound (I); and Isolating crystalline form B of compound (I) by filtration. Crystalline form B of compound (I), produced by a process comprising:

[0044] 23. Crystalline form C of compound (I): [ka] (In the formula, C * is a stereochemical center). 24. Crystalline form C according to embodiment 23, 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. 25. Crystalline form C according to embodiment 23 or 24, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 7. 26. Crystalline form C of any one of embodiments 23 to 25, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 118.5°C to about 119°C, and a DSC scan rate of 15°C / min. 27. Crystalline form C of any one of embodiments 23-26, characterized by a DSC thermogram showing an onset of melting at about 115.6°C to about 116°C, with a DSC scan rate of 15°C / min. 28. Crystalline form C of any one of embodiments 23 to 27, characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 120.5°C to about 121°C, and a DSC scan rate of 10°C / min. 29. Crystalline form C of any one of embodiments 23 to 28, characterized by a DSC thermogram showing an onset of melting at about 118°C to about 118.5°C, with a DSC scan rate of 10°C / min. 30. Crystalline form C according to any one of embodiments 23-29, wherein at least 95% of compound (I) is the (E) isomer. 31. Crystalline form C according to any one of embodiments 23 to 30, characterized in the P-1 space group. 32. What are the dimensions of the following unit cell at 200(2)K? a=10.6741Å α=93.654° b=12.7684Å β=104.400° c=14.5287Å γ=105.476° 32. Crystalline form C according to any one of embodiments 23 to 31, characterized in that: 33. Adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution; Seeding the solution with crystalline Form B of Compound (I) to form a mixture, and stirring the mixture to obtain a slurry; and Isolating crystalline form C by filtering the slurry. 2. Crystalline form C of compound (I), prepared by a process comprising: 34. At least one crystalline form of Compound (I) selected from the crystalline forms described in any one of embodiments 1 to 33; and at least one pharmaceutically acceptable excipient 10. A pharmaceutical composition comprising: 35. The pharmaceutical composition described in embodiment 34, in the form of a solid oral composition. 36. A pharmaceutical composition according to embodiment 34 or 35, in the form of a tablet or capsule. 37. A method of inhibiting Bruton's tyrosine kinase (BTK) in a mammal, comprising administering to the mammal in need of BTK inhibition a therapeutically effective amount of at least one crystalline form selected from the crystalline forms described in any one of embodiments 1-33. 38. A method of treating a disease mediated by Bruton's tyrosine kinase (BTK) in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms described in any one of embodiments 1-33. 39. A method for treating pemphigus vulgaris or pemphigus foliaceus in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms described in any one of embodiments 1 to 33. 40. A method for treating immune thrombocytopenia in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms described in any one of embodiments 1 to 33. 41. The method of any one of embodiments 37 to 40, wherein the mammal is a human.

[0045] Crystalline Form A of Compound (I) In some embodiments, the present disclosure provides crystalline Form A of Compound (I): [ka] (In the formula, * C is a stereochemical center).

[0046] Figure 1 shows the X-ray powder diffraction pattern for crystalline Form A of Compound (I). In Figure 1, the XRPD pattern corresponds to crystalline Form A containing a small amount of crystalline Form B, further described below.

[0047] 2 shows a DSC thermogram of crystalline form A of Compound (I). In some embodiments, crystalline form A of Compound (I) is characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 146°C to about 147°C. In some embodiments, crystalline form A of Compound (I) is characterized by a DSC thermogram showing an onset of melting / decomposition at about 140.6°C to about 141.2°C. In some embodiments, crystalline form A of Compound (I) is characterized by a DSC thermogram showing an onset of melting 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).

[0048] In some embodiments, crystalline Form A of Compound (I) is characterized by a DSC thermogram substantially similar to that of FIG.

[0049] In some embodiments, crystalline Form A of Compound (I) is characterized by a thermogravimetric analysis-Fourier transform infrared spectroscopy (TG-FTIR) thermal curve substantially similar to that of Figure 3. In some embodiments, crystalline Form A of Compound (I) is characterized by a mass loss of less than 1.0 wt.% between 25°C and 200°C by thermogravimetric analysis. In some embodiments, this mass loss corresponds to the loss of isopropyl acetate, which is released around the melting temperature. In some embodiments, decomposition is observed at higher temperatures (onset at about 220°C to about 230°C), for example, substantially as shown in Figure 3.

[0050] In some embodiments, crystalline Form A of Compound (I) has a water content of less than 1% upon storage at 85% relative humidity (RH).

[0051] In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis with an incident beam of Cu-Kα radiation having signals substantially similar to those set forth in Table 1.

[0052] [Table 1]

[0053] In some embodiments, crystalline form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 5.6±0.2°2-theta. In some embodiments, crystalline form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 12.7±0.2°2-theta. In some embodiments, crystalline form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.5±0.2°2-theta. In some embodiments, crystalline form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 17.0±0.2°2-theta. In some embodiments, crystalline form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 17.7±0.2°2-theta. In some embodiments, crystalline form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 17.7±0.2°2-theta. Form A is characterized by an X-ray powder diffractogram having a signal at 18.7±0.2°2-theta. In some embodiments, crystalline form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 19.2±0.2°2-theta. In some embodiments, crystalline form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.7±0.2°2-theta. In some embodiments, crystalline form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 22.2±0.2°2-theta. In some embodiments, crystalline form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 24.4±0.2°2-theta.

[0054] In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form A of Compound (I) 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, crystalline Form A of Compound (I) 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, crystalline Form A of Compound (I) 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, crystalline Form A of Compound (I) 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, crystalline Form A of Compound (I) 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, crystalline Form A of Compound (I) 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, crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals 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, crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals 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.

[0055] In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to that of FIG.

[0056] In some embodiments, the present disclosure provides a method for preparing crystalline Form A of Compound (I), comprising adding isopropyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution. In some embodiments, the method further comprises stirring the solution to form a precipitate. In some embodiments, the method further comprises isolating crystalline Form A by filtration.

[0057] In some embodiments, the present disclosure provides crystalline Form A of Compound (I), prepared by a process comprising adding isopropyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution. In some embodiments, the process further comprises stirring the solution to form a precipitate. In some embodiments, the process further comprises isolating crystalline Form A by filtration.

[0058] Crystalline form B of compound (I) In some embodiments, the present disclosure provides crystalline Form B of Compound (I): [ka] (In the formula, * C is a stereochemical center).

[0059] Figure 4A shows the X-ray powder diffraction pattern for crystalline Form B of Compound (I), which contains 95%-99% of the (E) isomer. In Figure 4A, the XRPD pattern corresponds to crystalline Form B obtained without NaCl seeding using seed crystals of crystalline Forms A and B that were added to a stirred solution of amorphous Compound (I) in ethyl acetate, followed by stirring overnight, which resulted in the crystallization and production of crystalline Form B.

[0060] Figure 4B shows the X-ray powder diffraction pattern for crystalline Form B of Compound (I), which contains greater than 99% of the (E) isomer. In Figure 4B, the XRPD pattern corresponds to crystalline Form B obtained without NaCl seeding using seed crystals of crystalline Form B added to a stirred slurry of Compound (I) Form C in ethanol, followed by stirring overnight, which resulted in the crystallization and production of crystalline Form B containing greater than 99% of the (E) isomer.

[0061] Crystalline form A can convert over time to crystalline form B. Thus, crystalline form B is It may be more thermodynamically stable than crystalline form A at room temperature.

[0062] Crystalline form C can convert over time to crystalline form B. Thus, crystalline form B may be thermodynamically more stable than crystalline form C at room temperature.

[0063] FIG. 5A shows the DSC thermogram of crystalline form B of Compound (I), which contains 95%-99% of the (E) isomer.

[0064] In some embodiments, crystalline form B of Compound (I) is characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 141° C. to about 142° C. In some embodiments, crystalline form B of Compound (I) is characterized by a DSC thermogram showing an onset of melting / decomposition at about 131.8° C. to about 132.4° C. In some embodiments, crystalline form B of Compound (I) is characterized by a DSC thermogram showing an onset of melting 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).

[0065] In some embodiments, crystalline Form B of Compound (I), comprising 95%-99% of the (E) isomer, is characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 141° C. to about 142° C. In some embodiments, crystalline Form B of Compound (I), comprising 95%-99% of the (E) isomer, is characterized by a DSC thermogram showing an onset of melting / decomposition at about 131.8° C. to about 132.4° C. In some embodiments, crystalline Form B of Compound (I), comprising 95%-99% of the (E) isomer, is characterized by a DSC thermogram showing an onset of melting 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).

[0066] In some embodiments, crystalline Form B of Compound (I) is characterized by a DSC thermogram substantially similar to that of Figure 5A. In some embodiments, crystalline Form B of Compound (I), comprising 95%-99% of the (E) isomer, is characterized by a DSC thermogram substantially similar to that of Figure 5A.

[0067] FIG. 5B shows the DSC thermogram of crystalline form B, which contains more than 99% of the (E) isomer.

[0068] In some embodiments, the crystalline form of Compound (I) is characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 144° C. to about 146° C. In some embodiments, crystalline Form B of Compound (I) is characterized by a DSC thermogram showing an onset of melting at about 139.3° C. In some embodiments, the associated enthalpy is about 65.5 J / g (ΔH=65.5 J / g).

[0069] In some embodiments, a crystalline form of Compound (I) comprising greater than 99% of the (E) isomer is characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 144° C. to about 146° C. In some embodiments, crystalline Form B of Compound (I) comprising greater than 99% of the (E) isomer is characterized by a DSC thermogram showing an onset of melting at about 139.3° C. In some embodiments, the associated enthalpy is about 65.5 J / g (ΔH=65.5 J / g).

[0070] In some embodiments, crystalline Form B of Compound (I) is characterized by a DSC thermogram substantially similar to that of Figure 5B. In some embodiments, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by a DSC thermogram substantially similar to that of Figure 5B.

[0071] In some embodiments, crystalline Form B of Compound (I) is characterized by a thermogravimetric analysis-Fourier transform infrared spectroscopy (TG-FTIR) heat curve substantially similar to that of Figure 6A. In some embodiments, crystalline Form B of Compound (I), comprising 95%-99% of the (E) isomer, is characterized by a thermogravimetric analysis-Fourier transform infrared spectroscopy (TG-FTIR) heat curve substantially similar to that of Figure 6A.

[0072] In some embodiments, crystalline Form B of Compound (I) is characterized by a mass loss of less than 0.8 wt.% between 25°C and 162°C by thermogravimetric analysis. In some embodiments, in addition to the mass loss described above, there is an additional mass loss of less than 0.8 wt.% between 162°C and 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 (onset at about 250°C to about 253°C), e.g., substantially as shown in Figure 6A.

[0073] In some embodiments, crystalline Form B of Compound (I), comprising 95%-99% of the (E) isomer, is characterized by a mass loss of less than 0.8 wt.% between 25°C and 162°C by thermogravimetric analysis. In some embodiments, in addition to the mass loss described above, there is an additional mass loss of less than 0.8 wt.% between 162°C and 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 (onset at about 250°C to about 253°C), e.g., substantially as shown in FIG. 6A.

[0074] In some embodiments, crystalline Form B of Compound (I) is characterized by a thermogravimetric analysis-Fourier transform infrared spectroscopy (TG-FTIR) heat curve substantially similar to that of Figure 6B. In some embodiments, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by a thermogravimetric analysis-Fourier transform infrared spectroscopy (TG-FTIR) heat curve substantially similar to that of Figure 6B.

[0075] In some embodiments, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by a mass loss of less than 0.7 wt.% between 25°C and 162°C by thermogravimetric analysis. In some embodiments, in addition to the mass loss described above, there is an additional mass loss of less than 0.7 wt.% between 162°C and 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 (onset at about 250°C to about 253°C), e.g., substantially as shown in FIG. 6A.

[0076] In some embodiments, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by a mass loss of less than 0.5 wt.% between 25°C and 162°C by thermogravimetric analysis. In some embodiments, in addition to the mass loss described above, there is an additional mass loss of less than 0.5 wt.% between 162°C and 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 (onset at about 250°C to about 253°C), e.g., substantially as shown in Figure 6B.

[0077] In some embodiments, crystalline Form B of Compound (I) is characterized by a water content of less than 1.3% upon storage at 95% relative humidity (RH). In some embodiments, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by a water content of less than 1.3% upon storage at 95% relative humidity (RH).

[0078] In some embodiments, crystalline Form B of Compound (I) is the same as those set forth in Table 2A. In some embodiments, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram produced by X-ray powder diffractometry with an incident beam of Cu-Kα radiation having signals substantially similar to those set forth in Table 2A.

[0079] [Table 2-1] [Table 2-2]

[0080] In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 10.8±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 15.3±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.3±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 17.9±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 18.4±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 18.7±0.2°2-theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 22.9±0.2 degrees two-theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 23.1±0.2 degrees two-theta.

[0081] In some embodiments, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 10.8±0.2°2-theta. In some embodiments, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 15.3±0.2°2-theta. In some embodiments, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 16.3±0.2°2-theta. In some embodiments, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 17.9±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 18.4±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 18.7±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 22.9±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 23.1±0.2°2-theta.

[0082] In some embodiments, the crystalline form B of Compound (I) has a pH 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, 19.8±0.2, 20.8±0.2, 21.6±0.2, 22.4±0.2, 23.2±0.2, 24.2±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0 In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals 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.

[0083] In some embodiments, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, 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. ... Crystalline Form B is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffractogram having signals 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, crystalline Form B of Compound (I), comprising 95-99% of the (E) isomer, is characterized by an X-ray powder diffraction pattern having signals 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.

[0084] In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4A. In some embodiments, crystalline Form B of Compound (I), comprising 95%-99% of the (E) isomer, is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4A.

[0085] In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis with an incident beam of Cu-Kα radiation having signals substantially similar to those set forth in Table 2B. In some embodiments, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram produced by X-ray powder diffractometry with an incident beam of Cu-Kα radiation having signals substantially similar to those set forth in Table 2B.

[0086] [Table 3-1] [Table 3-2]

[0087] In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram at 4.2±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 5.1±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 10.8±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 15.3±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.3±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 17.9±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 18.4±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 18.7±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 19.2±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 21.2±0.2°2-theta. In some embodiments, crystalline form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 22.0±0.2°2-theta. It can be characterized.

[0088] In some embodiments, crystalline form B of Compound (I), which contains more than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram at 4.2±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), which contains more than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 5.1±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), which contains more than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 10.8±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), which contains more than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 15.3±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), which contains more than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 16.3±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), which contains more than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 17.9±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), which contains more than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 18.4±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), which contains more than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 18.7±0.2°2-theta. In some embodiments, crystalline form B of Compound (I), which contains more than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 19.2±0.2°2-theta. In some embodiments, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 21.2±0.2 degrees two-theta. In some embodiments, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having a signal at 22.0±0.2 degrees two-theta.

[0089] In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least ten 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, crystalline Form B of Compound (I) 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, crystalline Form B of Compound (I) 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, crystalline Form B of Compound (I) 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, crystalline Form B of Compound (I) 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I) 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, crystalline Form B of Compound (I) 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals 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, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals 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.

[0090] In some embodiments, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram with 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, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by an X-ray powder diffraction pattern having signals at at least ten 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, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, 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, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, 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, crystalline Form B of Compound (I), which comprises greater than 99% of the (E) isomer, 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, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram having signals at at least six 2-theta values ​​selected from: 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, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by an X-ray powder diffractogram 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, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, 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, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, 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, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by an X-ray powder diffraction pattern having signals 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, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by an X-ray powder diffraction pattern having signals 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.

[0091] In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4B. In some embodiments, crystalline Form B of Compound (I), comprising greater than 99% of the (E) isomer, is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4B.

[0092] In some embodiments, the present disclosure provides crystalline Form B of Compound (I), prepared by a process comprising adding ethyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution. In some embodiments, the process further comprises seeding the solution with sodium chloride and stirring to obtain a suspension. In some embodiments, the process further comprises isolating crystalline Form B by filtering the suspension.

[0093] In some embodiments, the present disclosure provides a method for preparing crystalline Form B of Compound (I), comprising dissolving amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile in ethyl acetate to form a solution. In some embodiments, the method further comprises seeding the solution with crystalline Form A of Compound (I) and a mixture of crystalline Forms A and B of Compound (I) to obtain a slurry. In some embodiments, the method further comprises adding heptane to the slurry and filtering the slurry to obtain crystalline Form B of Compound (I).

[0094] In some embodiments, the present disclosure provides crystalline Form B of Compound (I), produced by a process comprising dissolving amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile in ethyl acetate to form a solution. In some embodiments, the process further comprises seeding the solution with crystalline Form A of Compound (I) and a mixture of crystalline Forms A and B of Compound (I) to obtain a slurry. In some embodiments, the process further comprises adding heptane to the slurry and filtering the slurry to obtain crystalline Form B of Compound (I).

[0095] In some embodiments, the present disclosure provides crystalline Form B of Compound (I) containing 95% to 99% of the (E) isomer, produced by a process comprising adding ethyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution. In some embodiments, the process further comprises seeding the solution with sodium chloride and stirring to obtain a suspension. In some embodiments, the process further comprises isolating crystalline Form B containing 95% to 99% of the (E) isomer by filtering the suspension.

[0096] In some embodiments, the present disclosure provides a method for preparing crystalline Form B of Compound (I) comprising 95% to 99% of the (E) isomer, comprising dissolving amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile in ethyl acetate to form a solution. In some embodiments, the method further comprises seeding the solution with crystalline Form A of Compound (I) and a mixture of crystalline Forms A and B of Compound (I) to obtain a slurry. In some embodiments, the method further comprises adding heptane to the slurry and filtering the slurry to obtain crystalline Form B of Compound (I) comprising 95% to 99% of the (E) isomer.

[0097] In some embodiments, the present disclosure provides crystalline Form B of Compound (I) comprising 95% to 99% of the (E) isomer, produced by a process comprising dissolving amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile in ethyl acetate to form a solution. In some embodiments, the process further comprises seeding the solution with crystalline Form A of Compound (I) and a mixture of crystalline Forms A and B of Compound (I) to obtain a slurry. In some embodiments, the process further comprises adding heptane to the slurry and filtering the slurry to obtain crystalline Form B of Compound (I) comprising 95% to 99% of the (E) isomer.

[0098] In some embodiments, the present disclosure provides a method for preparing crystalline form B of Compound (I), comprising dissolving crystalline form C of Compound (I) in ethanol to form a solution or slurry. In some embodiments, the method further comprises seeding the solution or slurry with crystalline form B of Compound (I). In some embodiments, the method further comprises obtaining a precipitate by filtration. In some embodiments, the method further comprises drying the precipitate under vacuum to obtain crystalline form B of Compound (I). In some embodiments, drying the precipitate under vacuum comprises applying heat. include.

[0099] In some embodiments, crystalline form C dissolves at about 15° C. In some embodiments, the solution or slurry seeded with crystalline form B is stirred at room temperature for a period of time, in some embodiments, about 48 hours.

[0100] In some embodiments, the present disclosure provides a method for preparing crystalline form B of Compound (I) comprising greater than 99% of the (E) isomer, comprising dissolving crystalline form C of Compound (I) in ethanol to form a solution or slurry. In some embodiments, the method further comprises seeding the solution or slurry with crystalline form B of Compound (I). In some embodiments, the method further comprises obtaining a precipitate by filtration. In some embodiments, the method further comprises drying the precipitate under vacuum to obtain crystalline form B of Compound (I) comprising greater than 99% of the (E) isomer. In some embodiments, drying the precipitate under vacuum comprises applying heat.

[0101] In some embodiments, crystalline form C dissolves at about 15° C. In some embodiments, the solution or slurry seeded with crystalline form B is stirred at room temperature for a period of time, in some embodiments, about 48 hours.

[0102] Crystalline form C of compound (I) In some embodiments, the present disclosure provides crystalline Form C of Compound (I): [ka] (In the formula, * C is a stereochemical center).

[0103] Crystalline form C is an acetonitrile solvate of compound (I).

[0104] FIG. 7 shows the X-ray powder diffraction diagram for crystalline Form C of Compound (I).

[0105] 8 shows a DSC thermogram of crystalline form C of Compound (I). In some embodiments, crystalline form C of Compound (I) is characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 118.5°C to about 119°C. In some embodiments, crystalline form C of Compound (I) is characterized by a DSC thermogram showing an onset of melting / decomposition at about 115.6°C to about 116.0°C. In some embodiments, crystalline form C of Compound (I) is characterized by a DSC thermogram showing an onset of melting at about 115.6°C to about 116.0°C.

[0106] 8 also shows the TGA thermal curve of crystalline form C of Compound (I). In some embodiments, crystalline form C is characterized by less than 5% mass loss between 25°C and 150°C.

[0107] The DSC thermograms in Figure 8 were obtained using a TA Instruments Q100 or Q2000 differential scanning calorimeter equipped with an autosampler and refrigeration system at 40 mL / min under an N2 purge. DSC thermograms of the screening samples were obtained at 15 °C / min in crimped Al pans. TGA thermograms were obtained on a TA Instruments Q50 thermogravimetric analyzer in Pt or Al pans at 40 mL / min under an N2 purge. TGA thermograms of the screening samples were obtained at 15 °C / min unless otherwise noted.

[0108] Figure 9 shows a different DSC thermogram of crystalline form C of Compound (I). The DSC conditions were the same as in Figure 8, except that the temperature scan rate was 10°C / min. In some embodiments, crystalline form C of Compound (I) is characterized by a DSC thermogram with an endothermic peak (melting temperature) at about 120.5°C to about 121°C. In some embodiments, crystalline form C of Compound (I) is characterized by a DSC thermogram showing an onset of melting / decomposition at about 118.0°C to about 118.5°C.

[0109] Figure 9 also shows the TGA thermal curve of crystalline form C of Compound (I). The TGA conditions were the same as in Figure 8, except that the temperature scan rate was 10°C / min. In some embodiments, crystalline form C is characterized by a mass loss of less than 5 wt.% between 25°C and 145°C. In some embodiments, the mass loss is due to removal of acetonitrile.

[0110] In some embodiments, Form C of Compound (I) decomposes at higher temperatures (above 250° C.), as shown, for example, in Figure 10, which is a TG-FTIR thermogram of crystalline Form C. Figure 10 also shows that there is less than 5.5% mass loss between 100° C. and 200° C. In some embodiments, the mass loss is due to loss of acetonitrile.

[0111] In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis with an incident beam of Cu-Kα radiation having signals substantially similar to those set forth in Table 3.

[0112] [Table 4-1] [Table 4-2]

[0113] In some embodiments, crystalline form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 9.8±0.2°2-theta. In some embodiments, crystalline form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 10.2±0.2°2-theta. In some embodiments, crystalline form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 15.6±0.2°2-theta. In some embodiments, crystalline form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.6±0.2°2-theta. In some embodiments, crystalline form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 18.6±0.2°2-theta. In some embodiments, crystalline form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 18.9±0.2°2-theta. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 19.6±0.2 degrees two-theta. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 21.6±0.2 degrees two-theta.

[0114] In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form C of Compound (I) 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. Crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram 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, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals 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.

[0115] In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to that of FIG.

[0116] In some embodiments, crystalline Form C of Compound (I) is characterized by a single crystal structure substantially similar to that of FIG.

[0117] In some embodiments, crystalline form C of Compound (I) is characterized in the P-1 space group.

[0118] In some embodiments, crystalline Form C of Compound (I) is characterized by the P-1 space group and the following unit cell dimensions: a=10.67Å α=93.65° b=12.77Å β=104.40° c=14.53Å γ=105.48°

[0119] In some embodiments, crystalline Form C of Compound (I) is characterized by the P-1 space group and the following unit cell dimensions: a=10.674Å α=93.654° b=12.768Å β=104.400° c=14.529Å γ=105.476°

[0120] In some embodiments, crystalline Form C of Compound (I) is characterized by the P-1 space group and the following unit cell dimensions: a=10.6741Å α=93.6543° b=12.7684Å β=104.4003° c=14.5287Å γ=105.4764°

[0121] In some embodiments, crystalline Form C of Compound (I) is characterized by the P-1 space group and the following unit cell dimensions: a=10.67411Å α=93.6543° b=12.76842Å β=104.4003° c=14.52872Å γ=105.4764°

[0122] In some embodiments, crystalline Form C of Compound (I) is characterized by the P-1 space group and the following unit cell dimensions: a=10.674113Å α=93.6543° b=12.768416Å β=104.4003° c=14.528715Å γ=105.4764°

[0123] In some embodiments, crystalline Form C of Compound (I) is characterized by the P-1 space group and the following unit cell dimensions at 200(2)K: a=10.67Å α=93.65° b=12.77Å β=104.40° c=14.53Å γ=105.48°

[0124] In some embodiments, crystalline Form C of Compound (I) is characterized by the P-1 space group and the following unit cell dimensions at 200(2)K: a=10.674Å α=93.654° b=12.768Å β=104.400° c=14.529Å γ=105.476°

[0125] In some embodiments, crystalline Form C of Compound (I) is characterized by the P-1 space group and the following unit cell dimensions at 200(2)K: a=10.6741Å α=93.6543° b=12.7684Å β=104.4003° c=14.5287Å γ=105.4764°

[0126] In some embodiments, crystalline Form C of Compound (I) is characterized by the P-1 space group and the following unit cell dimensions at 200(2)K: a=10.67411Å α=93.6543° b=12.76842Å β=104.4003° c=14.52872Å γ=105.4764°

[0127] In some embodiments, crystalline Form C of Compound (I) is characterized by the P-1 space group and the following unit cell dimensions at 200(2)K: a=10.674113Å α=93.6543° b=12.768416Å β=104.4003° c=14.528715Å γ=105.4764°

[0128] In some embodiments, the present disclosure provides a method for preparing crystalline Form C of Compound (I), comprising adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution. In some embodiments, the method further comprises seeding the solution with crystalline Form B of Compound (I) to form a mixture and stirring the mixture to obtain a slurry. In some embodiments, the method further comprises isolating crystalline Form C by filtering the slurry.

[0129] In some embodiments, the present disclosure provides a method for preparing amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d

[0010] Provided is crystalline Form C of Compound (I), produced by a process comprising adding crystalline Form B of Compound (I) to 4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (I) to form a solution. In some embodiments, the process further comprises adding crystalline Form B of Compound (I) as a seed to the solution to form a mixture and stirring the mixture to obtain a slurry. In some embodiments, the process further comprises isolating crystalline Form C by filtering the slurry.

[0130] In some embodiments, the present disclosure provides a method for preparing crystalline Form C of Compound (I), comprising adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution. In some embodiments, the method further comprises seeding the solution with crystalline Form C of Compound (I) and stirring to obtain a precipitate. In some embodiments, the method further comprises isolating crystalline Form C by filtering the precipitate. In some embodiments, the method further comprises drying the precipitate under vacuum to obtain crystalline Form C of Compound (I).

[0131] In some embodiments, the present disclosure provides crystalline Form C of Compound (I), produced by a process comprising adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution. In some embodiments, the process further comprises seeding the solution with crystalline Form C of Compound (I) and stirring to obtain a precipitate. In some embodiments, the process further comprises isolating crystalline Form C by filtering the precipitate. In some embodiments, the process further comprises drying the precipitate under vacuum to obtain crystalline Form C of Compound (I).

[0132] In some embodiments, the present disclosure provides a method for preparing crystalline Form C of Compound (I), comprising stirring a mixture of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and a mixture of crystalline Forms A and B of Compound (I) in an acetonitrile / t-butyl methyl ether mixture. In some embodiments, the method further comprises seeding the mixture with crystalline Form A, and optionally adding an additional amount of the acetonitrile / t-butyl methyl ether mixture to obtain a suspension. In some embodiments, the suspension is a thick suspension. In some embodiments, the method further comprises isolating crystalline Form C of Compound (I) by filtering the suspension.

[0133] In some embodiments, the present disclosure provides crystalline Form C of Compound (I), prepared by a process comprising stirring a mixture of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and a mixture of crystalline Forms A and B of Compound (I) in an acetonitrile / t-butyl methyl ether mixture. In some embodiments, the process comprises seeding the mixture with crystalline Form A, and optionally further adding an additional amount of the acetonitrile / t-butyl methyl ether mixture to obtain a suspension. In some embodiments, the suspension is a concentrated suspension. In some embodiments, the method further comprises isolating crystalline Form C of Compound (I) by filtering the suspension.

[0134] Indications The crystalline forms of Compound (I) described herein may be useful for treating conditions mediated by BTK activity in mammals. In some embodiments, the crystalline forms of Compound (I) described herein can be used to treat humans or non-humans.

[0135] The crystalline forms of Compound (I) described herein are useful in treating, for example, pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, alopecia areata, vitiligo vulgaris, pyoderma gangrenosum, mucous membrane pemphigoid, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, TEN (toxic epidermal necrolysis), drug eruption, folliculitis barbae, pseudofolliculitis barbae, leukocytoclastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, acne, mycosis fungoides, Sweet's syndrome, inflammatory bowel disease, arthritis, lupus, lupus nephritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, Sjogren's syndrome, multiple sclerosis, ankylosing spondylitis, and the like. spondylitis, scleroderma, Wegener's granulomatosis, psoriasis, asthma, colitis, conjunctivitis, dermatitis, uveitis, eczema, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma lymphoma) / Waldenstrom's 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's lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, and lymphomatoid granulomatosis.

[0136] Pemphigus is a rare B-cell-mediated autoimmune disease that causes debilitating intraepithelial blisters and erosions in the skin and / or mucous membranes. Pemphigus has a 10% mortality rate, typically due to infections and treatment side effects in affected tissues, affecting approximately 0.1–0.5 per 100,000 people annually (Scully et al., 2002; Scully et al., 1999). The characteristic intraepidermal blisters observed in pemphigus patients are caused by IgG autoantibodies binding to specific keratinocyte desmosomal adhesion proteins, desmogleins 1 and 3 (Dsg1 and Dsg3), resulting in loss of cell adhesion (Amagai M et al., 2012; Diaz LA et al., 2000). B cells play a key role in the production of these autoantibodies and in the cellular tolerance mechanisms.

[0137] Immune thrombocytopenia (commonly referred to as ITP) is characterized by autoantibody-mediated destruction of platelets and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding associated with morbidity and mortality. Preliminary evidence supports the role of BTK inhibition in patients with autoimmune cytopenia, as consecutive episodes of severe autoimmune hemolytic anemia and ITP terminated after initiation of treatment with the BTK / EGFR / ITK inhibitor ibrutinib in patients with chronic lymphocytic leukemia (CLL) (Rogers, 2016; Montillo, 2017).

[0138] Pharmaceutical Composition The crystalline forms described herein are useful as active pharmaceutical ingredients (APIs) and as materials for preparing pharmaceutical compositions that incorporate one or more pharmaceutically acceptable excipients and are suitable for administration to human subjects. In some embodiments, these pharmaceutical compositions are formulated as solid oral dosage forms, such as, for example, tablets and / or capsules. It is a pharmaceutical product.

[0139] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one crystalline form of Compound (I). In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one crystalline form of Compound (I) and at least one additional pharmaceutically acceptable excipient. Each excipient must be "pharmaceutically acceptable," in the sense of being compatible with the subject composition and not harmful to the patient. Use of any conventional pharmaceutically acceptable excipient is considered within the scope of the present disclosure unless it is incompatible with Compound (I), e.g., by producing any undesirable biological effect or by interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition.

[0140] Some non-limiting examples of materials that can serve as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) additives, such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances utilized in pharmaceutical formulations.

[0141] Remington: The Science and Practice of Pharmacy, 21st ed., 2005, D.B. Troy, ed., Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J.C.B. Boylan, eds., 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference, also disclose additional non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for making and using them.

[0142] The pharmaceutical compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions of the present disclosure are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the pharmaceutical compositions of the present disclosure may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable excipients or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0143] For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. It can be. Fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injectables, as are pharmaceutically acceptable natural oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol excipients or dispersants such as carboxymethylcellulose, or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Spans, and other emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0144] The pharmaceutical compositions disclosed herein can also be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or liquids.When aqueous suspensions are required for oral use, active ingredient is typically combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavoring agents or coloring agents can also be added.

[0145] Alternatively, the pharmaceutical compositions disclosed herein can be administered in the form of suppositories for rectal administration.Suppositories can be prepared by mixing the drug with suitable non-irritating additives that are solid at room temperature but liquid at rectal temperature, and therefore melt in the rectum to release the drug.Such materials include but are not limited to cocoa butter, beeswax, and polyethylene glycol.

[0146] The pharmaceutical composition of the present disclosure can also be administered locally, especially when the target of treatment includes areas or organs that can be easily accessed by topical application, including diseases of the eye, skin, or lower intestinal tract.Suitable topical formulations are easily prepared for each of these areas or organs.Topical application to the lower intestinal tract can be carried out in a rectal suppository formulation or a suitable enema formulation.Topical transdermal patches can also be used.

[0147] For topical application, pharmaceutical compositions can be formulated with suitable ointments, which contain active ingredients suspended or dissolved in at least one additive.The additives for topical administration of the compounds of the present disclosure include but are not limited to mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, pharmaceutical compositions disclosed herein can be formulated with suitable lotions or creams, which contain active ingredients suspended or dissolved in at least one pharmaceutically acceptable additive.Suitable additives include but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0148] The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, utilizing benzyl alcohol or other suitable preservatives, absorption enhancers which enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0149] dosage In general, the crystalline forms of Compound (I) are administered in a therapeutically effective amount by any of the applicable modes of administration for drugs serving similar utilities. The effective dose for any particular mammal (e.g., any particular human) will depend on the disorder being treated and the severity of the disorder; the particular pharmaceutical composition being utilized; the mammal's age, weight, general health, sex, and diet; the time of administration, the route of administration, the duration of treatment; and similar factors well known in the medical arts. The therapeutically effective amount of at least one crystalline form of Compound (I) is administered to a mammal in need thereof, depending on various factors. In some embodiments, a therapeutically effective amount of at least one crystalline form of Compound (I) is administered to a mammal in need thereof. A therapeutically effective amount of the crystalline forms disclosed herein can range, for example, from 0.01 to 500 mg / kg of patient body weight per day, which can be administered in single or multiple doses. Suitable dosage levels can 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 this range, in some embodiments, the dosage can 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 can be provided in the form of a tablet containing 1.0 to 1000 milligrams of active ingredient, for example, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient.

[0150] Generally, the crystalline forms of the present disclosure are administered as pharmaceutical compositions by any one of the following routes: oral; systemic (e.g., transdermal, intranasal, or suppository); topical; or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. For example, the composition may take the form of a tablet, capsule, semisolid, powder, sustained-release formulation, enteric-coated or delayed-release formulation, liquid, suspension, elixir, aerosol, or any other suitable composition.

[0151] All publications and patents mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0152] A claim or description including "or" or "and / or" between at least one member of a group is considered to be satisfied when one, more than one, or all of the group members are present in, utilized in, or relevant to a given product or process, unless otherwise indicated or otherwise clear from the context. The present disclosure includes embodiments in which exactly one member of a group is present in, utilized in, or relevant to a given product or process. The present disclosure includes embodiments in which two or more or all group members are present in, utilized in, or relevant to a given product or process.

[0153] Furthermore, the present disclosure encompasses 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 that depends on another claim can be amended to include at least one limitation found in any other claim that depends from the same basic claim. When elements are presented as a list, for example, in Markush group format, each subgroup of elements is also disclosed, and any element can be removed from the group. In general, when the present disclosure or aspects of the present disclosure are referred to as including particular elements and / or features, it should be understood that embodiments of the present disclosure or aspects of the present disclosure consist of or consist essentially of such elements and / or features. For simplicity, these embodiments are not specifically described in these terms herein. When ranges are presented, endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can take any specific value or subrange within the ranges described in different embodiments of this disclosure, to an accuracy of one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0154] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. It is intended to be encompassed by the following claims. [Example]

[0155] The following examples are intended to be illustrative and are not meant to limit the scope of the present disclosure in any way.

[0156] Analysis method 1: X-ray powder diffraction X-ray powder diffraction can be performed on a Stoe Stadi P diffractometer equipped with a Mythen 1K detector operating with Cu-Kα1 radiation. Measurements on this instrument can be performed with a tube voltage of 40 kV and a tube power of 40 mA. A curved Ge monochromator can be used for testing with Cu-Kα1 radiation. The following parameters are set: a step size of 0.02°2θ, a step time of 12 seconds, a scan range of 1.5 to 50.5°2θ, and a detector step of 1°2θ (detector mode in step scan). For a typical sample preparation, approximately 10 mg of sample is placed between two acetate membranes and mounted in a Stoe transmission sample holder. The sample is rotated during the measurement. All sample preparation and measurements can be performed under ambient air.

[0157] Analysis Method 2: X-ray Powder Diffraction (PXRD) PANalytical PXRD diffractograms can be obtained on a PANalytical X'Pert Pro diffractometer using Ni-filtered Cu-Ka (45 kV / 40 mA) radiation and a 0.03°2q step size, and an X'celerator™ RTMS (Real Time Multi-Strip) detector. The incident beam configuration can be a variable divergence slit (10 mm exposure length), a 0.04 rad Soller slit, a fixed anti-scatter slit (0.50°), and a 10 mm beam mask. The diffraction beam configuration can be a variable anti-scatter slit (10 mm observation length) and a 0.04 rad Soller slit. Samples are mounted flat on a zero-background Si wafer.

[0158] Analysis Method 3: Differential Scanning Calorimetry (DSC) DSC can be performed on a TA Instruments Q100 or Q2000 differential scanning calorimeter equipped with an autosampler and refrigeration cooling system at 40 mL / min under a N2 purge. DSC thermograms of screening samples can be obtained in crimped aluminum pans at 15 °C / min.

[0159] Analysis method 4: Thermogravimetric analysis (TGA) TGA thermograms can be obtained on a TA Instruments Q50 thermogravimetric analyzer in Pt or Al pans at 40 mL / min under a N purge. TGA thermograms of screening samples can be obtained at 15°C / min.

[0160] Analysis Method 5: Thermogravimetric Analysis with IR Off-Gas Detection (TGA-IR) TGA-IR was performed on a TA Instruments Q5000 thermogravimetric analyzer connected to a Nicolet 6700 FT-IR spectrometer (Thermo Electron) equipped with an external TGA-IR module with a gas flow cell and a DTGS detector. TGA was performed in Pt or Al pans with an N flow of 25 mL / min and a heating rate of 15 °C / min. IR spectra were recorded at 4 cm intervals at each time point.-1 resolution and 32 scans can be collected.

[0161] Analysis method 6: Fourier transform infrared spectroscopy (TG-FTIR) Thermogravimetry was performed using a Bruker FTIR Spectrometer Vector Netzsch Thermo-Microbalance TG 2 coupled to 22 09 (sample pan with pinhole, N2 atmosphere, heating rate 10 °C / min).

[0162] Common methods: Several crystallization experiments were performed as part of the polymorph studies for Compound (I). The experiments included different crystallization techniques such as suspension equilibrium experiments, precipitation, cooling crystallization, and vapor diffusion experiments. [Example]

[0163] Preparation of crystalline form A of compound (I) 98 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile was dissolved in 400 μL of isopropyl acetate at room temperature. After stirring for 1 day, a very thick 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. [Example]

[0164] Preparation of Crystalline Form B of Compound (I) Containing 95% to 99% of the (E) Isomer 96 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile was dissolved in 0.3 mL of ethyl acetate. The resulting solution was seeded with NaCl and stirred at room temperature. After stirring overnight, a cloudy 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. [Example]

[0165] Alternative Preparation of Crystalline Form B of Compound (I) Containing 95% to 99% of the (E) Isomer 3.64 g of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile was dissolved in ethyl acetate (EtOAc) (11 mL) at room temperature (RT) and seeded with crystalline form A (20 mg) and a mixture of crystalline forms A and B (60 mg). The seed crystals were retained. 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 give 3.5 g of crystalline form B (94% yield). [Example]

[0166] Alternative preparation of crystalline form B of compound (I) containing more than 99% of the (E) isomer 430 g of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (Compound (I)) Form C was combined with ethanol (4.1 L) at approximately 15° C. to form a slurry. Seed crystals of Form B were then added (to approximately 5 wt.%) and the slurry was stirred for approximately 2 days. The slurry was filtered and dried under vacuum with heating to provide approximately 300 g of crystalline Form B of Compound (I) (74% yield). [Example]

[0167] Preparation of crystalline form C of compound (I) 100 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile was combined with acetonitrile (MeCN) (0.5 mL; 5 vol). The solution was seeded with crystalline Form B of Compound (I) and stirred at room temperature for 48 hours. At approximately 48 hours, a thick, white, free-flowing slurry was obtained, determined to be crystalline Form C. Estimated yield: >50%. [Example]

[0168] Alternative Preparation 1 of Crystalline Form C of Compound (I) 61.2 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and 49.8 mg of a mixture of crystalline forms A and B were suspended in 400 μL of a 1:1 acetonitrile / t-butyl methyl ether (TBME) mixture at room temperature. After stirring for 10 minutes, the suspension was seeded with crystalline form A. After stirring overnight at room temperature, an additional 400 μL of a 1:1 acetonitrile / TBME mixture was added. After stirring for 5 days at room temperature, a very thick suspension was obtained, and 600 μL of a 1:1 acetonitrile / TBME mixture was added. After a total of 2 weeks of stirring, the suspension was filtered (centrifugal unit filter, PTFE, 0.22 μm) and the recovered solid was air-dried for approximately 1 hour to obtain crystalline form C. [Example]

[0169] Alternative Preparation 2 of Crystalline Form C of Compound (I) 9.3 g of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile was combined with MeCN (93 mL; 10 vol). The solution was seeded with crystalline form C (35 mg) and stirred at room temperature for 72 hours. A precipitate was observed after 2 hours. The solid was isolated via filtration and dried under vacuum at 30° C. for 1 hour to give crystalline form C. Yield: 76%. [Example]

[0170] Alternative Preparation 3 of Crystalline Form C of Compound (I) 100 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile was combined with MeCN / MTBE (1:1; 1.4 mL). Seed crystals of crystalline form B were added to the solution. The seeds dissolved. The solution was then added with a mixture of seed crystals of crystalline forms A and B and stirred for 48 hours. No significant precipitation was observed. Seed crystals of crystalline form C were then added to the solution. Some thickening was observed. The solution was stirred for 5 days, and the precipitate obtained by filtration was crystalline form C. Yield: 42%. [Example]

[0171] Single crystal X-ray diffraction Compound (I) (10.2 mg) was dissolved in the internal solvent (acetonitrile) in a vial, which was then placed in a larger vial containing the external solvent (isopropyl ether) and allowed to stand at 4°C for 15 days to grow a single crystal. Single crystal X-ray diffraction data were obtained using a Bruker D8 Venturi using graphite monochromator MoKα (λ = 0.71073 Å) radiation. Crystals were collected on a re DUO diffractometer. Crystals were mounted on a MiTeGen MicroMount and collected at 200(2)K using an Oxford Cryosystems 800 cryodevice. Data were collected using Omega and Phi scans and corrected for Lorentzian and polarization effects using the APEX3 software suite and published routines in WinGX (Farrugia, 2005). All images were generated using Ortep-3 for Windows.

[0172] The single crystal exhibited the P-1 space group, which contains the triclinic crystal system. The following unit cell dimensions were measured: a=10.6741(13)Å α=93.654(3)° b=12.7684(16)Å β=104.400(3)° c=14.5287(15)Å γ=105.476(4)°

Claims

1. Crystalline Form A of Compound (I): 【Chemistry 1】 (In the formula, C ＊ is a stereochemical center).

2. 2. The crystalline form A of claim 1, 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.

3. 3. Crystalline form A according to claim 1 or 2, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 1.

4. 4. Crystalline form A according to any one of claims 1 to 3, characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 146°C to about 147°C.

5. 5. The crystalline form A of any one of claims 1 to 4, characterized by a DSC thermogram showing an onset of melting at about 140.6°C to about 141.2°C.

6. 6. Crystalline form A according to any one of claims 1 to 5, characterized by a mass loss of less than 1.0 wt. % between 25°C and 200°C by thermogravimetric analysis.

7. Crystalline form A according to any one of claims 1 to 6, characterized by a water content of less than 1% upon storage at 95% relative humidity (RH).

8. The crystalline form A according to any one of claims 1 to 7, wherein at least 95% of compound (I) is the (E) isomer.

9. Crystalline form A of compound (I), adding isopropyl acetate to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution; stirring the solution to form a precipitate; and Isolating crystalline form A by filtration Crystalline form A produced by a process comprising:

10. Crystalline form B of compound (I): 【Chemistry 2】 (In the formula, C ＊ is a stereochemical center).

11. 11. The crystalline form B of claim 10, 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, 22.0±0.2, and 22.9±0.

2.

12. 12. The crystalline form B of claim 10 or 11, wherein at least 99% of compound (I) is the (E) isomer.

13. 12. Crystalline form B according to claim 10 or 11, wherein 95% to 99% of compound (I) is the (E) isomer.

14. 13. Crystalline form B according to any one of claims 10 to 12, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4B.

15. 14. The crystalline form B of any one of claims 10, 11, or 13, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4A.

16. 15. Crystalline form B of any one of claims 10 to 12, or 14, characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 144°C to about 146°C.

17. 17. The crystalline form B of any one of claims 10-12, 14, or 16, characterized by a DSC thermogram showing an onset of melting at about 139.3°C.

18. 16. The crystalline form B of any one of claims 10, 11, 13, or 15, characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 141°C to about 142°C.

19. 19. The crystalline form B of any one of claims 10, 11, 13, 15, or 18, characterized by a DSC thermogram that exhibits an onset of melting at about 131.8°C to about 132.4°C.

20. Crystalline form B according to any one of claims 10 to 19, characterized by a water content of less than 1.3% upon storage at 95% relative humidity (RH).

21. Crystalline form B of compound (I), Ethyl acetate was added to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl ] to pent-2-enenitrile to form a solution; Seeding the solution with sodium chloride and stirring the solution to obtain a suspension; Isolating crystalline form B by filtration of the suspension. Crystalline form B produced by a process comprising:

22. Crystalline form B of compound (I), adding ethanol to (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile Form C to form a solution or slurry; Seeding the solution or slurry with Form B of Compound (I); and Isolating crystalline form B of compound (I) by filtration. Crystalline form B produced by a process comprising:

23. Crystalline form C of compound (I): 【Transformation 3】 (In the formula, C ＊ is a stereochemical center).

24. 24. The crystalline form C of claim 23, 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.

25. 25. Crystalline form C according to claim 23 or 24, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 7.

26. 26. Crystalline form C according to any one of claims 23 to 25, characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 118.5°C to about 119°C, and a DSC scan rate of 15°C / min.

27. 27. Crystalline form C according to any one of claims 23 to 26, characterized by a DSC thermogram showing an onset of melting at about 115.6°C to about 116°C, with a DSC scan rate of 15°C / min.

28. 28. Crystalline form C according to any one of claims 23 to 27, characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 120.5°C to about 121°C, and a DSC scan rate of 10°C / min.

29. 29. The crystalline form of any one of claims 23 to 28, characterized by a DSC thermogram showing an onset of melting at about 118°C to about 118.5°C, with a DSC scan rate of 10°C / min. C.

30. 30. Crystalline form C according to any one of claims 23 to 29, wherein at least 95% of compound (I) is the (E) isomer.

31. Crystalline form C according to any one of claims 23 to 30, characterized in the P-1 space group.

32. The following unit cell dimensions at 200(2) K: a=10.6741Å α=93.654° b=12.7684Å β=104.400° c=14.5287Å γ=105.476° 32. Crystalline form C according to any one of claims 23 to 31, characterized in that:

33. Crystalline form C of compound (I), adding acetonitrile to amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to form a solution; Seeding the solution with crystalline Form B of Compound (I) to form a mixture, and stirring the mixture to obtain a slurry; and Isolating crystalline form C by filtering the slurry. Crystalline form C produced by a process comprising:

34. 1. A pharmaceutical composition comprising: At least one crystalline form of compound (I) selected from the crystalline forms according to any one of claims 1 to 33; and at least one pharmaceutically acceptable excipient 10. A pharmaceutical composition comprising:

35. 35. The pharmaceutical composition of claim 34, in the form of a solid oral composition.

36. 36. The pharmaceutical composition of claim 34 or 35, in the form of a tablet or capsule.

37. 34. A method of inhibiting Bruton's tyrosine kinase (BTK) in a mammal, comprising administering to a mammal in need of BTK inhibition a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of claims 1-33.

38. 34. A method of treating a disease mediated by Bruton's tyrosine kinase (BTK) in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of claims 1 to 33.

39. 34. A method of treating pemphigus vulgaris or pemphigus foliaceus in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of claims 1 to 33.

40. 34. A method of treating immune thrombocytopenia in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of claims 1 to 33.

41. The method according to any one of claims 37 to 40, wherein the mammal is a human.

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