Crystalline forms of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4,4-dimethylpent-2-enenitrile

Abstract

To provide crystalline forms that are useful for large-scale manufacturing, pharmaceutical formulation, and / or storage.SOLUTION: There is provided a crystalline form (I) of the compound (I) shown below characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2, and 22.1±0.2.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 958,389 (filed January 8, 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-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (Compound (I)), methods of using them, and methods of 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 multiple 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, IBD, lupus, and asthma).

[0004] Compound (I) and its various solid forms can inhibit BTK and may be useful in treating disorders and conditions mediated by BTK activity. Compound (I) is disclosed, for example, as compound 125A in Table 1 of U.S. Patent No. 5,929,999, and has the following structure: [ka] It has.

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

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

[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 forms will exhibit desirable properties. Because different solid forms (e.g., crystalline forms) can 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] WO2012 / 158764 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, of Compound (I), which are useful for treating disorders and conditions mediated by BTK activity, and reproducible and scalable methods for 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 preparing the same. In some embodiments, the novel crystalline forms disclosed herein have properties useful for large-scale manufacturing, pharmaceutical formulation, and / or storage. In some embodiments, the novel crystalline forms disclosed herein consist of a single crystalline form. In some embodiments, the crystalline form is substantially pure.

[0011] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a pharmaceutically acceptable excipient; and at least one crystalline form selected from crystalline forms of Compound (I). In some embodiments, at least one crystalline form is crystalline Form (I) of Compound (I). In some embodiments, at least one crystalline form is crystalline Form (II) of Compound (I). In some embodiments, at least one crystalline form is crystalline Form (III) of Compound (I). In some embodiments, at least one crystalline form is crystalline Form (IV) of Compound (I). In some embodiments, at least one crystalline form is crystalline Form (V) of Compound (I).

[0012] Some embodiments of the present disclosure relate to methods of inhibiting BTK in a mammal in need thereof by administering 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 (I) of Compound (I). In some embodiments, the at least one crystalline form is crystalline Form (II) of Compound (I). In some embodiments, the at least one crystalline form is crystalline Form (III) of Compound (I). In some embodiments, the at least one crystalline form is crystalline Form (IV) of Compound (I). In some embodiments, the at least one crystalline form is crystalline Form (V) of Compound (I).

[0013] In some embodiments, the mammal in need of BTK inhibition has a BTK-mediated In some embodiments, the BTK-mediated disease is pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, alopecia areata, vitiligo, pyoderma gangrenosum, membrane pemphigoid, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug eruption, folliculitis barbae, pseudofolliculitis barbae, leucoclastic vasculitis, hidradenitis suppurativa, palmar-plantar pustulosis, or the like. 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 The tumor is selected from: idiopathic 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 selected from pemphigus vulgaris. In some embodiments, the BTK-mediated disease is selected from pemphigus foliaceus.

[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 is a method for producing at least one crystalline form selected from the crystalline forms of Compound (I). Some embodiments of the present disclosure relate to the above method, wherein at least one crystalline form is crystalline form (I) of Compound (I). Some embodiments of the present disclosure relate to the above method, wherein at least one crystalline form is crystalline form (II) of Compound (I). Some embodiments of the present disclosure relate to the above method, wherein at least one crystalline form is crystalline form (III) of Compound (I). Some embodiments of the present disclosure relate to the above method, wherein at least one crystalline form is crystalline form (IV) of Compound (I). Some embodiments of the present disclosure relate to the above method, wherein at least one crystalline form is crystalline form (V) of Compound (I).

[0017] In some embodiments, the method includes temperature cycling a slurry containing Compound (I). In some embodiments, the slurry containing Compound (I) is cycled between 5°C and 40°C. In some embodiments, the slurry containing Compound (I) is cycled between 5°C and 40°C for 36 hours. In some embodiments, the slurry containing Compound (I) is cycled between 5°C and 40°C for 36 hours. In some embodiments, the slurry is equilibrated after temperature cycling. In some embodiments, the slurry is equilibrated at 25°C. In some embodiments, the slurry is equilibrated for 8 hours. In some embodiments, the slurry further comprises at least one solvent selected from 1-butanol, 1-methoxy-2-propanol, 1-propanol, 2-methoxyethanol, 2-methoxyethyl ether, 4-methyl-2-pentanone acetone, acetonitrile, butyl acetate, cyclohexane, cyclopentyl methyl ether, ethanol, ethyl acetate, heptane, isopropyl acetate, isopropyl ether, isopropyl ethyl ether, methanol, nitromethane, N,N-dimethylformamide, t-butyl methyl ether, trifluoroethanol, and water.

[0018] In some embodiments, the method includes rapidly cooling a clarified saturated solution comprising Compound (I). In some embodiments, the clarified saturated solution comprising Compound (I) is rapidly cooled from 25° C. to 4° C. In some embodiments, the clarified saturated solution comprising Compound (I) is maintained after rapid cooling. In some embodiments, the clarified saturated solution comprising Compound (I) is maintained at 4° C. In some embodiments, the clarified saturated solution comprising Compound (I) is maintained for 48 hours. In some embodiments, the clarified saturated solution comprising Compound (I) is maintained at 4° C. for 48 hours. In some embodiments, the clarified saturated solution comprising Compound (I) further comprises 2-butanone.

[0019] In some embodiments, the method includes slowly evaporating a solution comprising Compound (I). In some embodiments, the solution comprising Compound (I) is slowly evaporated for up to 10 days. In some embodiments, the solution comprising Compound (I) further comprises at least one solvent selected from 1-butanol, 1-methoxy-2-propanol, 2-methyltetrahydrofuran, 1-propanol, 2-butanone, 2-methoxyethanol, acetone, acetonitrile, cyclopentyl methyl ether, ethanol, ethyl acetate, isopropyl acetate, isopropyl ether, methanol, nitromethane, toluene, and water. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 shows an X-ray powder diffractogram of crystalline Form (I) of Compound (I), herein referred to as crystalline Form (I), with degrees (2θ (2 theta)) on the X-axis and relative intensity on the Y-axis. [Figure 2] FIG. 2 shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) heat curve for crystalline Form (I) of Compound (I). [Figure 3]FIG. 3 shows an X-ray powder diffractogram for crystalline Form (II) of Compound (I), herein referred to as crystalline Form (II), with degrees (2θ (2 theta)) on the X-axis and relative intensity on the Y-axis. [Figure 4] FIG. 4 shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) heat curve for crystalline Form (II) of Compound (I). [Figure 5] FIG. 5 shows an X-ray powder diffractogram for crystalline Form (III) of Compound (I), herein referred to as crystalline Form (III), with degrees (2θ (2 theta)) on the X-axis and relative intensity on the Y-axis. [Figure 6] FIG. 6 shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) heat curve for crystalline Form (III) of Compound (I). [Figure 7] FIG. 7 shows an X-ray powder diffractogram for crystalline Form (IV) of Compound (I), herein referred to as crystalline Form (IV), with degrees (2θ (2 theta)) on the X-axis and relative intensity on the Y-axis. [Figure 8] FIG. 8 shows the thermogravimetric analysis (TGA) thermal curve for crystalline Form (IV) of Compound (I). [Figure 9] FIG. 9 shows an X-ray powder diffractogram for crystalline Form (V) of Compound (I), herein referred to as crystalline Form (V), with degrees (2θ (2 theta)) on the X-axis and relative intensity on the Y-axis. [Figure 10] FIG. 10 shows the thermogravimetric analysis (TGA) thermal curve for crystalline form (V) of Compound (I). DETAILED DESCRIPTION OF THE INVENTION

[0021] Embodiments: Non-limiting embodiments of the present disclosure include: 1. Compound (I): [ka] The crystalline form of (I).

[0022] 2. Crystalline form (I) according to embodiment 1, characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2, and 22.1±0.2.

[0023] 3. Crystalline form (I) according to embodiment 1, characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in FIG.

[0024] 4. Crystalline form (I) according to any one of embodiments 1 to 3, characterized by a DSC thermogram with a peak endotherm (melting point) at about 177°C to about 178°C.

[0025] 5. Crystalline form (I) according to any one of embodiments 1 to 4, characterized by a DSC thermogram showing an onset of melting at about 174.8°C to about 175.2°C.

[0026] 6. The crystalline form (I) according to any one of embodiments 1 to 5, wherein at least 95% by weight of compound (I) is the (E) isomer.

[0027] 7. The crystalline form (I) of any one of embodiments 1 to 6, wherein at least 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0028] 8. adding methyl isobutyl ketone to amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile to form a solution; Stirring the solution to form a precipitate; and Isolating the crystalline form (I) by filtration 1. A crystalline form (I) of compound (I) prepared by a process comprising:

[0029] 9. Compound (I): [ka] The crystalline form of (II).

[0030] 10. Crystalline form (II) according to embodiment 9, characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.2.

[0031] 11. Crystalline form (II) according to embodiment 9, characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in Figure 3.

[0032] 12. Crystalline Form (II) according to any one of embodiments 9 to 11, characterized by a DSC thermogram with a peak endotherm (melting point) at about 170.0°C to about 170.2°C.

[0033] 13. Crystalline Form (II) according to any one of embodiments 9 to 12, characterized by a DSC thermogram showing an onset of melting at about 167.2°C to about 167.6°C.

[0034] 14. Crystalline form (II) according to any one of embodiments 9 to 13, characterized by a mass loss by thermogravimetric analysis of less than 1.5% by weight between 35°C and 220°C.

[0035] 15. Crystalline form (II) according to any one of embodiments 9 to 14, wherein at least 95% by weight of compound (I) is the (E) isomer.

[0036] 16. The crystalline form (II) of any one of embodiments 9 to 15, wherein at least 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0037] 17. Dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl t-butyl ether to form a solution; stirring the solution to form a precipitate; and Isolating the crystalline form (II) by filtration 2. A crystalline form (II) of compound (I) prepared by a process comprising:

[0038] 18. Compound (I): [ka] The crystalline form (III) of

[0039] 19. Crystalline form (III) according to embodiment 18, characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 10.3±0.2, 15.1±0.2, 16.5±0.2, 17.6±0.2, 20.0±0.2, and 22.5±0.2.

[0040] 20. Crystalline form (III) according to embodiment 18, characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in Figure 5.

[0041] 21. Crystalline Form (III) according to any one of embodiments 18-20, characterized by a DSC thermogram with a peak endotherm (melting point) at about 167.4°C to about 167.8°C.

[0042] 22. Crystalline Form (III) according to any one of embodiments 18 to 21, characterized by a DSC thermogram showing an onset of melting at about 165.1°C to about 165.5°C.

[0043] 23. Crystalline form (III) according to any one of embodiments 18 to 22, wherein at least 95% by weight of compound (I) is the (E) isomer.

[0044] 24. The crystalline form (III) of any one of embodiments 18-23, wherein at least 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0045] 25. Dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl t-butyl ether; and Isolating the crystalline form (III) by filtration. 1. A crystalline form (III) of compound (I) prepared by a process comprising:

[0046] 26. Compound (I): [ka] Crystalline form (IV).

[0047] 27. Crystalline form (IV) according to embodiment 26, characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 20.2±0.2, 20.3±0.2, and 24.2±0.2.

[0048] 28. Crystalline form (IV) according to embodiment 26, characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in FIG. 7.

[0049] 29. Crystalline form (IV) according to any one of embodiments 26 to 28, characterized by a mass loss of less than 14% by weight between 70°C and 180°C by thermogravimetric analysis.

[0050] 30. Crystalline form (IV) according to any one of embodiments 26 to 29, wherein at least 95% by weight of compound (I) is the (E) isomer.

[0051] 31. Crystalline Form (IV) of any one of embodiments 26-30, wherein at least 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0052] 32. Dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in 2-methyl-1-propanol to form a solution; filtering the solution; and Isolating crystalline form (IV) by evaporating 2-methyl-1-propanol. 1. A crystalline form (IV) of compound (I) prepared by a process comprising:

[0053] 33. Compound (I): [ka] The crystalline form of (V).

[0054] 34. The crystalline form (V) of embodiment 33, characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 4.7±0.2, 6.5±0.2, 14.2±0.2, 16.2±0.2, 16.5±0.2, 19.8±0.2, and 20.7±0.2.

[0055] 35. Crystalline form (V) according to embodiment 33, characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in Figure 9.

[0056] 36. Crystalline form (V) according to any one of embodiments 33 to 35, characterized by a mass loss of less than 7% by weight between 75°C and 110°C by thermogravimetric analysis.

[0057] 37. Crystalline form (V) according to any one of embodiments 33 to 36, wherein at least 95% by weight of compound (I) is the (E) isomer.

[0058] 38. Crystalline form (V) of any one of embodiments 33-37, wherein at least 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0059] 39. Dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in toluene to form a solution; filtering the solution; and Isolating the crystalline form (V) by evaporating the toluene. 2. A crystalline form (V) of compound (I) prepared by a process comprising:

[0060] 40. at least one pharmaceutically acceptable excipient; and At least one crystalline form selected from the crystalline forms of any one of embodiments 1 to 39. 10. A pharmaceutical composition comprising:

[0061] 41. A method of inhibiting Bruton's tyrosine kinase (BTK) in a mammal in need thereof, comprising administering a therapeutically effective amount of any one of embodiments 1-39. The method comprises administering to said mammal at least one crystalline form selected from the group consisting of:

[0062] 42. A method for treating a disease mediated by 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 1-39.

[0063] 43. Diseases include pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, alopecia areata, vitiligo, pyoderma gangrenosum, pemphigoid membranes, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), 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, scleroderma, Wegener's granulomatosis, psoriasis, asthma, colitis, and conjunctival 43. The method of embodiment 42, wherein the tumor is selected from: inflammation, dermatitis, uveitis, eczema, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell 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.

[0064] 44. The method of any one of embodiments 41 to 43, wherein the mammal is a human.

[0065] 45. Adding methyl isobutyl ketone to amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile to form a solution; Stirring the solution to form a precipitate; and Isolating the crystalline form (I) by filtration 1. A process for producing crystalline form (I) of compound (I), comprising:

[0066] 46. ​​Dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl t-butyl ether to form a solution; stirring the solution to form a precipitate; and Isolating the crystalline form (II) by filtration 1. A process for producing crystalline form (II) of compound (I), comprising:

[0067] 47. Dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl t-butyl ether; and Isolating the crystalline form (III) by filtration. 1. A process for preparing crystalline form (III) of compound (I), comprising:

[0068] 48. Amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile was dissolved in 2-methyl-1-propanoic acid. dissolving in alcohol to form a solution; filtering the solution; and Isolating crystalline form (IV) by evaporating 2-methyl-1-propanol. 1. A process for producing crystalline form (IV) of compound (I), comprising:

[0069] 49. Dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in toluene to form a solution; filtering the solution; and Isolating the crystalline form (V) by evaporating the toluene. 1. A process for producing crystalline form (V) of compound (I), comprising:

[0070] Definition: As used herein, "a" or "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 specified. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0071] As used herein, the term "about" or "approximately" means in the region of, roughly, or in the region of. When the term "about" is used in conjunction 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 above and below the stated value by a variance of 5%.

[0072] As used herein, “Compound (I)” refers to a compound having the following structure: [ka] [where *C is a stereochemical center] and (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, It refers to a mixture of the (R) and (S) enantiomers of (azolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0073] When compound (I) is designated as (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, it may contain the corresponding (S) enantiomer as an impurity at less than 1% by weight. Thus, when compound (I) is designated as a mixture of the (R) and (S) enantiomers of 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, the amount of the (R) or (S) enantiomer in the mixture is greater than 1% by weight. Similarly, when compound (I) is designated as the (E) isomer, it may contain the corresponding (Z) isomer as an impurity at less than 1% by weight. Thus, when compound (I) is designated as a mixture of the (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, the amount of the (E) or (Z) isomer in the mixture is greater than 1% by weight.

[0074] In some embodiments, compound (I) is a mixture of the (R) and (S) enantiomers of 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0075] In some embodiments, compound (I) is substantially (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile. In some embodiments, compound (I) is at least 75% by weight, e.g., at least 80% by weight, at least 85% by weight, at least 90% by weight, or at least 95% by weight (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile. In some embodiments, compound (I) is at least 95% by weight (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0076] Compound (I) may be referred to herein as a "drug," "active agent," "therapeutically active agent," or "API."

[0077] As used herein, "substantially pure" in reference to geometric isomers refers to a compound, such as Compound (I), in which greater than 70% by weight of the compound is present as a given isomer. For example, the phrase "Crystalline Form (I) of Compound (I) is a substantially pure (E) isomer of Compound (I)" refers to crystalline Form (I) of Compound (I) having at least 70% by weight of crystalline Form (I) of Compound (I) as the (E) isomer, and the phrase "Crystalline Form (I) of Compound (I) is a substantially pure (Z) isomer of Compound (I)" refers to crystalline Form (I) of Compound (I) having at least 70% by weight of crystalline Form (I) of Compound (I) as the (Z) isomer. In some embodiments, at least 80% by weight of the crystalline form of Compound (I) is the (E) isomer, or at least 80% by weight of the crystalline form of Compound (I) is the (Z) isomer. 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 (E) form. 5% by weight are the (Z) form. In some embodiments, at least 90% by weight of the crystalline forms of Compound (I) are the (E) form, or at least 90% by weight of the crystalline forms of Compound (I) are the (Z) form. In some embodiments, at least 95% by weight of the crystalline forms of Compound (I) are the (E) form, or at least 95% by weight of the crystalline forms of Compound (I) are the (Z) form. In some embodiments, at least 97% by weight of the crystalline forms of Compound (I) are the (E) form, or at least 97% by weight of the crystalline forms of Compound (I) are the (Z) form. In some embodiments, at least 98% by weight of the crystalline forms of Compound (I) are the (E) form, or at least 98% by weight of the crystalline forms of Compound (I) are the (Z) form. In some embodiments, at least 99% by weight of the crystalline forms of Compound (I) are the (E) form, or at least 99% by weight of the crystalline forms of Compound (I) are 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.

[0078] In some embodiments, compound (I) is a mixture of the (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0079] In some embodiments, compound (I) is a substantially pure (E) isomer of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile. In some embodiments, compound (I) is at least 75% by weight, e.g., at least 80% by weight, at least 85% by weight, at least 90% by weight, or at least 95% by weight, of the (E) isomer of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile. In some embodiments, compound (I) is at least 95% by weight of the (E) isomer of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0080] 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 crystalline 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 diffractogram having at least one signal at at least one specified two-theta value (°2θ).

[0081] As used herein, "pharmaceutically acceptable excipient" refers to a carrier or excipient that is useful in preparing pharmaceutical compositions. For example, pharmaceutically acceptable excipients include carriers and excipients that are generally considered safe and acceptable for mammalian pharmaceutical use.

[0082] As used herein, a "therapeutically effective amount" of a compound disclosed herein refers to an amount of the compound that elicits a biological or medical response in a subject. The therapeutically effective amount will depend on the purpose of the treatment and can be ascertained by one skilled in the art (see, for example, Lloyd (1999) The Art, Science and Technology of See Pharmaceutical Compounding).

[0083] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction 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.

[0084] As used herein, when used in reference to a disorder or condition, the terms "treat," "treating," or "treatment" include any effect that results in an improvement of the disorder or condition, e.g., lowering, reducing, modulating, ameliorating, or eliminating. Improvement in any symptoms of the disorder or condition or a decrease in their severity can be readily assessed according to standard methods and techniques known in the art.

[0085] As used herein, "mammal" refers to domestic animals (e.g., dogs, cats, and horses) and humans. In some embodiments, the mammal is a human. In some embodiments, the mammal is a dog.

[0086] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0087] As used herein, the term "TGA" refers to the analytical method of thermogravimetric (also called thermogravimetric) analysis.

[0088] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded using a diffractometer in transmission or reflection geometry at ambient conditions.

[0089] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," and "XRPD pattern" refer to an experimentally obtained pattern plotting signal position (on the abscissa) against signal intensity (on the ordinate). For a crystalline material, an X-ray powder diffractogram may contain at least one signal, each identified by its angular value measured in degrees 2θ (°2θ) shown on the abscissa of the X-ray powder diffractogram, which may be expressed as "signal at ... degrees (2-theta)," "at a 2-theta value of ...," and / or "signal at at least a 2-theta value selected from ...."

[0090] As used herein, the term "X-ray powder diffractogram having signals at 2-theta values ​​of ..." refers to an XRPD pattern containing the X-ray reflection positions (° 2θ) measured and observed in an X-ray powder diffraction experiment.

[0091] As used herein, the term "signal" refers to a point in an XRPD pattern where the intensity, as measured by counts, is a maximum. Those skilled in the art will appreciate that at least one signal in an XRPD pattern may overlap and may not be visible, for example, to the naked eye. Those skilled in the art will appreciate that several art-recognized methods are capable of and suitable for determining whether a signal is present in a pattern, such as, for example, Rietveld refinement.

[0092] As used herein, the terms "signal at ... degrees (2-theta)," "signal at a 2-theta value of ...," and "signal at at least a 2-theta value selected from ..." refer to the X-ray reflection positions (°2θ) measured and observed in an X-ray powder diffraction experiment. In some embodiments, the reproducibility of angle values ​​is within ±0.2°2θ, i.e., the angle value can be the stated angle value +0.2 degrees 2-theta, the angle value -0.2 degrees 2-theta, or between the two endpoints (angle value +0.2 degrees 2-theta and angle value -0.2 degrees 2-theta). Those skilled in the art are aware that there can be variability in the measured X-ray powder diffraction signal values. Thus, those skilled in the art will appreciate that there can be variability of up to ±0.2°2θ in the signal values ​​for the same signal in different samples. Furthermore, those skilled in the art are aware that there can be variability in the measured relative signal intensities in X-ray powder diffraction experiments. 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).

[0093] As used herein, an X-ray powder diffractogram is "substantially similar to the X-ray powder diffractogram in a [particular] view" 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 degrees 2θ. In determining "substantial similarity," one skilled in the art will appreciate that even for the same crystalline form, there may be variability in intensity and / or signal location in XRPD diffractograms. Thus, one skilled in the art will appreciate that signal maxima (referred to herein as degrees 2θ (°2θ)) in an XRPD diffractogram generally refer to the reported value ±0.2 degrees 2θ, an art-recognized difference as discussed above.

[0094] As mentioned above, novel crystalline forms of Compound (I) are described herein. These may be inhibitors of BTK. BTK inhibitors are useful in the treatment of BTK-mediated diseases, such as pemphigus vulgaris and pemphigus foliaceus.

[0095] Crystalline Form (I) of Compound (I) In some embodiments, the present disclosure provides compound (I): [ka] The present invention provides a crystalline form (I) of the formula:

[0096] FIG. 1 shows the X-ray powder diffractogram for crystalline Form (I) of Compound (I).

[0097] 2 shows a DSC thermogram of crystalline Form (I) of Compound (I). In some embodiments, crystalline Form (I) of Compound (I) is characterized by a DSC thermogram with a peak endotherm (melting point) at about 177°C to about 178°C. In some embodiments, crystalline Form (I) of Compound (I) is characterized by a DSC thermogram showing an onset of melting / decomposition at about 174.8°C to about 175.2°C. In some embodiments, crystalline Form (I) of Compound (I) is characterized by a DSC thermogram showing an onset of melting at about 174.8°C to about 175.2°C. In some embodiments, the associated enthalpy is about 85 J / g (ΔH=85 J / g).

[0098] In some embodiments, crystalline Form (I) of Compound (I) is characterized by a DSC thermogram substantially similar to the DSC thermogram in FIG.

[0099] FIG. 2 also shows the TGA thermal curve for crystalline Form (I) of Compound (I).

[0100] In some embodiments, crystalline Form (I) of Compound (I) is a white solid.

[0101] In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 1.

[0102] [Table 1-1] [Table 1-2]

[0103] In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 6.3±0.2 degrees 2-theta. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 12.6±0.2 degrees 2-theta. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.2±0.2 degrees 2-theta. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray diffractogram having a signal at 17.6±0.2 degrees 2-theta. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray diffractogram having a signal at 18.2±0.2 degrees 2-theta. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 18.4±0.2 degrees 2-theta. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 22.1±0.2 degrees 2-theta.

[0104] In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals at 2-theta values ​​of 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2, and 22.1±0.2. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least six 2-theta values ​​selected from 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2, and 22.1±0.2. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least five 2-theta values ​​selected from 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2, and 22.1±0.2. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least four 2-theta values ​​selected from 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2, and 22.1±0.2. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2, and 22.1±0.2. In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least two 2-theta values ​​selected from 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2, and 22.1±0.2. In some embodiments, the crystalline Form (I) of Compound (I) has at least one selected from 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2, and 22.1±0.2. The powder is characterized by an X-ray powder diffractogram with a signal at 2-theta values ​​of .

[0105] In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in FIG.

[0106] In some embodiments, the present disclosure provides a method for preparing crystalline Form (I) of Compound (I). In some embodiments, the present disclosure provides crystalline Form (I) of Compound (I) prepared by a method comprising adding methyl isobutyl ketone to amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile to form a solution. In some embodiments, the method further comprises agitating the solution to form a precipitate. In some embodiments, the method further comprises isolating crystalline Form (I) by filtration.

[0107] Crystalline Form (II) of Compound (I) In some embodiments, the present disclosure provides compound (I): [ka] The present invention provides a crystalline form (II) of the formula:

[0108] FIG. 3 shows the X-ray powder diffractogram for crystalline form (II) of compound (I).

[0109] 4 shows a DSC thermogram of crystalline Form (II) of Compound (I). In some embodiments, crystalline Form (II) of Compound (I) is characterized by a DSC thermogram with a peak endotherm (melting point) at about 170.0°C to about 170.2°C. In some embodiments, crystalline Form (II) of Compound (I) is characterized by a DSC thermogram showing an onset of melting / decomposition at about 167.2°C to about 167.6°C. In some embodiments, the association enthalpy is about 68 J / g (ΔH=68 J / g).

[0110] In some embodiments, crystalline Form (II) of Compound (I) is characterized by a DSC thermogram substantially similar to the DSC thermogram in FIG.

[0111] 4 also shows the TGA thermal curve for crystalline Form (II) of Compound (I). In some embodiments, crystalline Form (II) of Compound (I) is characterized by a mass loss of less than 1.5% by weight between 35° C. and 220° C. by thermogravimetric analysis.

[0112] Crystalline form (II) cannot be converted to crystalline form (I) by heating and cooling.

[0113] In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 2.

[0114] [Table 2-1] [Table 2-2]

[0115] In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 6.3±0.2 degrees 2-theta. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 15.2±0.2 degrees 2-theta. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.0±0.2 degrees 2-theta. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.6±0.2 degrees 2-theta. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 17.7±0.2 degrees 2-theta. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.0±0.2 degrees 2-theta. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 24.8±0.2 degrees 2-theta. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 27.5±0.2 degrees 2-theta.

[0116] In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals at 2-theta values ​​of 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.2. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least seven 2-theta values ​​selected from 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.2. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least six 2-theta values ​​selected from 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.2. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least five 2-theta values ​​selected from 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.2. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least four 2-theta values ​​selected from 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.2. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.2. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least two 2-theta values ​​selected from 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.2. In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least one 2-theta value selected from 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.2.

[0117] In some embodiments, crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in FIG.

[0118] In some embodiments, the present disclosure provides a method for preparing crystalline Form (II) of Compound (I). In some embodiments, the present disclosure provides crystalline Form (II) of Compound (I), prepared by a process comprising dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl t-butyl ether 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 (II) by filtration.

[0119] Crystalline Form (III) of Compound (I) In some embodiments, the present disclosure provides compound (I): [ka] The present invention provides a crystalline form (III) of the formula:

[0120] FIG. 5 shows an X-ray powder diffractogram of crystalline form (III) of compound (I). Indicates the system.

[0121] 6 shows a DSC thermogram of crystalline Form (III) of Compound (I). In some embodiments, crystalline Form (III) of Compound (I) is characterized by a DSC thermogram with a peak endotherm (melting point) at about 167.4°C to about 167.8°C. In some embodiments, crystalline Form (III) of Compound (I) is characterized by a DSC thermogram showing an onset of melting / decomposition at about 165.1°C to about 165.5°C. In some embodiments, crystalline Form (III) of Compound (I) is characterized by a DSC thermogram showing an onset of melting at about 165.1°C to about 165.5°C. In some embodiments, the association enthalpy is about 66.3 J / g (ΔH=66.3 J / g).

[0122] In some embodiments, crystalline Form (III) of Compound (I) is characterized by a DSC thermogram substantially similar to the DSC thermogram in FIG.

[0123] 6 also shows the TGA thermal curve for crystalline Form (III) of Compound (I). In some embodiments, crystalline Form (III) of Compound (I) is characterized by a mass loss of less than 0.6% by weight between 50° C. and 190° C. by thermogravimetric analysis.

[0124] In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 3.

[0125] [Table 3]

[0126] In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 10.3±0.2 degrees 2-theta. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 15.1±0.2 degrees 2-theta. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.5±0.2 degrees 2-theta. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 17.6±0.2 degrees 2-theta. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.0±0.2 degrees 2-theta. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 22.5±0.2 degrees 2-theta.

[0127] In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having signals at 2-theta values ​​of 10.3±0.2, 15.1±0.2, 16.5±0.2, 17.6±0.2, 20.0±0.2, and 22.5±0.2. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least five 2-theta values ​​selected from 10.3±0.2, 15.1±0.2, 16.5±0.2, 17.6±0.2, 20.0±0.2, and 22.5±0.2. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least four 2-theta values ​​selected from 10.3±0.2, 15.1±0.2, 16.5±0.2, 17.6±0.2, 20.0±0.2, and 22.5±0.2. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 10.3±0.2, 15.1±0.2, 16.5±0.2, 17.6±0.2, 20.0±0.2, and 22.5±0.2. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least two 2-theta values ​​selected from 10.3±0.2, 15.1±0.2, 16.5±0.2, 17.6±0.2, 20.0±0.2, and 22.5±0.2. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least one 2-theta value selected from 10.3±0.2, 15.1±0.2, 16.5±0.2, 17.6±0.2, 20.0±0.2, and 22.5±0.2.

[0128] In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in FIG.

[0129] In some embodiments, the present disclosure provides a method for preparing crystalline Form (III) of Compound (I). In some embodiments, the present disclosure provides crystalline Form (III) of Compound (I) prepared by a method comprising dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl t-butyl ether. In some embodiments, the method further comprises isolating crystalline Form (III) by filtration.

[0130] Crystalline Form (IV) of Compound (I) In some embodiments, the present disclosure provides compound (I): [ka] The present invention provides a crystalline form (IV) of the formula:

[0131] FIG. 7 shows the X-ray powder diffractogram for crystalline Form (IV) of Compound (I).

[0132] 8 shows the TGA thermal curve for crystalline Form (IV) of Compound (I). In some embodiments, crystalline Form (IV) of Compound (I) is characterized by a mass loss of less than 14% by weight between 70° C. and 180° C. by thermogravimetric analysis.

[0133] In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 4.

[0134] [Table 4-1] [Table 4-2]

[0135] In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 4.7±0.2 degrees 2-theta. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 6.6±0.2 degrees 2-theta. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 6.8±0.2 degrees 2-theta. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 13.4±0.2 degrees 2-theta. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 13.5±0.2 degrees 2-theta. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.1±0.2 degrees 2-theta. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.2±0.2 degrees 2-theta. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.3±0.2 degrees 2-theta. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 24.2±0.2 degrees 2-theta.

[0136] In some embodiments, the crystalline form (IV) of Compound (I) has a pH of 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 21.1±0.2, 22.1±0.2, 23.1±0.2, 24.1±0.2, 25.1±0.2, In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least eight 2-theta values ​​selected from 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 20.2±0.2, 20.3±0.2, and 24.2±0.2. ... In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least seven 2-theta values ​​selected from: 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 20.2±0.2, 20.3±0.2, and 24.2±0.2. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least six 2-theta values ​​selected from: 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 20.2±0.2, 20.3±0.2, and 24.2±0.2. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least five 2-theta values ​​selected from: 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 20.2±0.2, 20.3±0.2, and 24.2±0.2. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least four 2-theta values ​​selected from: 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 20.2±0.2, 20.3±0.2, and 24.2±0.2.In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 20.2±0.2, 20.3±0.2, and 24.2±0.2. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least two 2-theta values ​​selected from 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 20.2±0.2, 20.3±0.2, and 24.2±0.2. In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one 2-theta value selected from 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 20.2±0.2, 20.3±0.2, and 24.2±0.2.

[0137] In some embodiments, crystalline Form (IV) of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in FIG.

[0138] In some embodiments, the present disclosure provides a method for preparing crystalline Form (IV) of Compound (I). In some embodiments, the present disclosure provides crystalline Form (IV) of Compound (I) prepared by a method comprising: dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in 2-methyl-1-propanol to form a solution. In some embodiments, the method further comprises filtering the solution. In some embodiments, the method further comprises isolating crystalline Form (IV) by evaporating the 2-methyl-1-propanol.

[0139] Crystalline Form (V) of Compound (I) In some embodiments, the present disclosure provides compound (I): [ka] The present invention provides a crystalline form (V) of the formula:

[0140] FIG. 9 shows the X-ray powder diffractogram for crystalline Form (V) of Compound (I).

[0141] 10 shows the TGA thermal curve for crystalline Form (V) of Compound (I). In some embodiments, crystalline Form (V) of Compound (I) is characterized by a mass loss of less than 7% by weight between 75° C. and 110° C. by thermogravimetric analysis.

[0142] In some embodiments, crystalline Form (V) of Compound (I) is a white solid.

[0143] In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 5.

[0144] [Table 5]

[0145] In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 4.7±0.2 degrees 2-theta. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 6.5±0.2 degrees 2-theta. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 14.2±0.2 degrees 2-theta. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.2±0.2 degrees 2-theta. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.5±0.2 degrees 2-theta. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 19.8±0.2 degrees 2-theta. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.7±0.2 degrees 2-theta.

[0146] In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having signals at 2-theta values ​​of 4.7±0.2, 6.5±0.2, 14.2±0.2, 16.2±0.2, 16.5±0.2, 19.8±0.2, and 20.7±0.2. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least six 2-theta values ​​selected from 4.7±0.2, 6.5±0.2, 14.2±0.2, 16.2±0.2, 16.5±0.2, 19.8±0.2, and 20.7±0.2. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least five 2-theta values ​​selected from: 4.7±0.2, 6.5±0.2, 14.2±0.2, 16.2±0.2, 16.5±0.2, 19.8±0.2, and 20.7±0.2. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least four 2-theta values ​​selected from: 4.7±0.2, 6.5±0.2, 14.2±0.2, 16.2±0.2, 16.5±0.2, 19.8±0.2, and 20.7±0.2. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from: 4.7±0.2, 6.5±0.2, 14.2±0.2, 16.2±0.2, 16.5±0.2, 19.8±0.2, and 20.7±0.2. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least two 2-theta values ​​selected from: 4.7±0.2, 6.5±0.2, 14.2±0.2, 16.2±0.2, 16.5±0.2, 19.8±0.2, and 20.7±0.2. In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one 2-theta value selected from 4.7±0.2, 6.5±0.2, 14.2±0.2, 16.2±0.2, 16.5±0.2, 19.8±0.2, and 20.7±0.2.

[0147] In some embodiments, crystalline Form (V) of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in FIG.

[0148] In some embodiments, the present disclosure provides a method for preparing crystalline Form (V) of Compound (I). In some embodiments, the present disclosure provides crystalline Form (V) of Compound (I) prepared by a method comprising: dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in toluene to form a solution. In some embodiments, the method further comprises filtering the solution. In some embodiments, the method further comprises isolating crystalline Form (V) by evaporating the toluene.

[0149] 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 may be useful for treating conditions mediated by BTK activity in mammals. The crystalline forms of Compound (I) described in can be used to treat humans or non-humans.

[0150] The crystalline forms of Compound (I) described herein are useful in treating a variety of conditions, including, for example, pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, alopecia areata, vitiligo, pyoderma gangrenosum, pemphigoid membranes, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug eruption, folliculitis barbae, pseudofolliculitis hair folliculitis, 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, scleroderma, Wegener's granulomatosis, psoriasis, and psoriasis. It may be useful in treating a variety of conditions or diseases such as 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 / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodular 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.

[0151] Pemphigus is a rare B cell-mediated autoimmune disease that causes debilitating intraepithelial blisters and erosions on the skin and / or mucous membranes. Pemphigus has a 10% mortality rate, usually due to infection arising from compromised tissues and treatment side effects, and affects approximately 0.1–0.5 per 100,000 people annually (Scully et al., 2002; Scully et al., 1999). The characteristic intraepidermal blisters seen in pemphigus patients are caused by IgG autoantibody 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 cellular tolerance mechanisms.

[0152] Immune thrombocytopenia (commonly referred to as ITP) is characterized by autoantibody-mediated destruction of platelets and impaired platelet production, which results in thrombocytopenia and a bleeding tendency accompanied by morbidity and mortality. Preliminary evidence supports the role of BTK inhibition in patients with autoimmune cytopenia (Rogers 2016, Montillo 2017), and sequential episodes of severe autoimmune hemolytic anemia and ITP ceased after initiation of treatment with the BTK / EGFR / ITK inhibitor ibrutinib in a patient with chronic lymphocytic leukemia (CLL).

[0153] Pharmaceutical Composition The crystalline forms described herein are useful not only as active pharmaceutical ingredients (APIs), but also as materials for preparing pharmaceutical compositions incorporating one or more pharmaceutically acceptable excipients and suitable for administration to human subjects. In some embodiments, these pharmaceutical compositions are pharmaceutical products, such as solid oral dosage forms, e.g., tablets and / or capsules.

[0154] 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 composition of interest, and its components must not be harmful to the patient. Any conventional pharmaceutically acceptable excipient may be used without, for example, causing any undesirable biological effects. Except where such use is incompatible with Compound (I), by producing adverse effects or by interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, such use is deemed to be within the scope of this disclosure.

[0155] Some non-limiting examples of substances that can function 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) excipients, such as cocoa butter and suppository wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and damascena. (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, 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 used in pharmaceuticals.

[0156] Remington: The Science and Practice of Pharmacy, 21st ed., 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference, also disclose further non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for making and using them.

[0157] The pharmaceutical compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" 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 diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0158] For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersants such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tween and Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0159] 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 ingredients are typically combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavoring agents or coloring agents can also be added.

[0160] 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 a suitable irritable excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0161] The pharmaceutical compositions of the present disclosure can also be administered topically, especially when the target of treatment includes areas or organs that are easily accessible 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 for the lower intestinal tract can be achieved with a rectal suppository formulation or a suitable enema.Topical transdermal patches may also be used.

[0162] For topical application, pharmaceutical compositions can be formulated with a suitable ointment containing the active ingredient suspended or dissolved in at least one excipient.Excipients for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, pharmaceutical compositions disclosed herein can be formulated with a suitable lotion or cream containing the active ingredient suspended or dissolved in at least one pharmaceutically acceptable excipient.Suitable excipients include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0163] 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 pharmaceutical formulation art and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers which enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0164] dosage In general, crystalline forms of Compound (I) are administered in therapeutically effective amounts by any of the accepted modes of administration for drugs serving similar utilities. The effective dose for any particular mammal (e.g., any particular human) will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the particular pharmaceutical composition used; the mammal's age, weight, overall health, sex, and diet; the time of administration, route of administration, duration of treatment; and similar factors well known in the medical field. In some embodiments, a therapeutically effective amount of at least one crystalline form of Compound (I) is administered to a mammal in need thereof. The therapeutically effective amount of the crystalline forms disclosed herein can range from 0.01 to 500 mg per kg of patient body weight per day, which can be administered in a single dose 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 may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, in some embodiments, the composition may be provided in the form of a tablet containing 1.0 to 1000 milligrams of the active ingredient, for example, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient.

[0165] Generally, the crystalline forms of the present disclosure are administered as a pharmaceutical composition by any one of the following routes: orally; systemically (e.g., transdermally, intranasally, or via suppository); topically; or parenterally (e.g., intramuscularly, intravenously, or subcutaneously). By way of example, the composition can take the form of a tablet, capsule, semisolid, powder, sustained-release formulation, enteric-coated or delayed-release formulation, solution, suspension, elixir, aerosol, or any other appropriate composition.

[0166] 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.

[0167] 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 members of the group are present in, used in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise apparent from the context. The disclosure includes embodiments in which exactly one member of a group is present in, used in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one or all of a group are present in, used in, or otherwise relevant to a given product or process.

[0168] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, or limiting term from at least one of the enumerated claims is inserted into another claim. For example, any claim that depends on another claim can be modified to include at least one limitation found in any other claim that depends from the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of those elements is also disclosed, and any element can be removed from the group. It should be understood that, generally, when a disclosure, or an aspect of a disclosure, is referred to as including certain elements and / or features, an embodiment of the disclosure or aspect of the disclosure consists of or consists essentially of such elements and / or features. For purposes of brevity, these embodiments are not specifically described in these terms herein. Where ranges are presented, the endpoints are included. Furthermore, unless otherwise indicated or clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can take any particular value or subrange within the ranges set forth in various embodiments of this disclosure, down to one-tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0169] 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. Such equivalents are intended to be encompassed by the following claims. [Example]

[0170] The following examples are intended to be illustrative and are not meant to limit the scope of the disclosure in any way.

[0171] Analysis method 1: Powder X-ray diffraction Powder X-ray diffraction was performed using a Stoecher equipped with a Mythen 1K detector operating at Cu-Kα1 radiation. Measurements using this instrument can be performed in transmission at 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 can be set: 0.02° 2θ step size, 12 s step time, 1.5-50.5° 2θ scan range, and 1° 2θ detector step (detector mode with step scan). Typical sample preparation To measure the sample, approximately 10 mg of sample is placed between two sheets of acetate foil 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 conditions.

[0172] Analysis Method 2: Powder X-ray Diffraction (PXRD) PANalytical PXRD diffractograms were obtained on a PANalytical X'Pert Pro diffractometer using Cu Ka (45 kV / 40 mA) radiation with a Ni filter and a step size of 0.03°2q and an X'celerator TM The images can be acquired using a RTMS (Real Time Multi-Strip) detector. The configuration on the incident beam side can be: variable dispersion slit (10 mm exposure length), 0.04 rad Soller slit, fixed anti-scatter slit (0.50°), and 10 mm beam mask. The configuration on the diffracted beam side can be: variable anti-scatter slit (10 mm observation length) and 0.04 rad Soller slit. The sample is mounted flat on a zero-background Si wafer.

[0173] Analysis Method 3: Differential Scanning Calorimetry (DSC) DSC can be performed using a TA Instruments Q100 or Q2000 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under a 40 mL / min N purge. DSC thermograms of screening samples can be obtained in crimped Al pans at 15°C / min.

[0174] Analysis method 4: Thermogravimetric analysis (TGA) TGA thermograms can be obtained in Pt or Al pans under a 40 mL / min N purge using a TA Instruments Q50 thermogravimetric analyzer. TGA thermograms of screening samples can be obtained at 15° C. / min.

[0175] Analysis Method 5: Thermogravimetric Analysis with IR Off-Gas Detection (TGA-IR) TGA-IR can be performed using a TA Instruments Q5000 thermogravimetric analyzer coupled to a Nicolet 6700 FT-IR spectrometer (Thermo Electron) equipped with an external TGA-IR module using a gas flow cell and a DTGS detector. TGA can be performed in Pt or Al pans with a 25 mL / min N2 flow and a heating rate of 15 °C / min. IR spectra can be measured using a 4 cm -1 resolution and 32 scans can be collected at each time point.

[0176] General method: To obtain multiple crystalline forms of Compound (I), a crystal form screen of Compound (I) was conducted using multiple solvents and three different crystallization techniques. Briefly, the three different crystallization techniques were thermal cycling (TC), rapid cooling (RC), and slow evaporation (EV). To prepare crystalline forms of Compound (I) by thermal cycling, a slurry containing Compound (I) was repeatedly changed in temperature between 5°C and 40°C for 36 hours, followed by equilibration at 25°C for 8 hours. To prepare crystalline forms of Compound (I) by rapid cooling, a clarified saturated solution of Compound (I) was rapidly cooled from 25°C to 4°C and held at 4°C for 48 hours. To prepare crystalline forms of Compound (I) by slow evaporation, a solution containing Compound (I) was slowly evaporated for up to 10 days. The solvents and solvent systems that yielded crystalline forms (I), (II), and (V) are listed in Table 6 below.

[0177] [Table 6-1] [Table 6-2]

[0178] Example 1: Preparation of crystalline form (I) of compound (I) Methyl isobutyl ketone (MIBK; 6 mL) was added to amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (1.0 g) and stirred to form a solution. After stirring for about 5 minutes, a precipitate began to form. Additional MIBK (10 mL) was charged and the slurry was stirred. After about 10 days, the solid was filtered and rinsed with MIBK (10 mL). The solid was dried under vacuum with heat to provide about 0.5 g of crystalline Form (I) of Compound (I) as a white solid.

[0179] Example 2: Preparation of Crystalline Form (II) of Compound (I) Amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (1.0 g) was dissolved in methyl t-butyl ether (MTBE, 4 mL). The solution was stirred at room temperature. After about 5 minutes, a precipitate began to form. Additional MTBE (about 10 mL) was added to the slurry. The solid was filtered and dried under vacuum to yield about 0.7 g of crystalline Form (II) of Compound (I).

[0180] Example 3: Preparation of crystalline form (III) of compound (I) Amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonitrile (I)-4,4-dimethylpent-2-enenitrile was dissolved in methyl t-butyl ether (MTBE). The solution was stirred at room temperature. The solid was filtered and dried under vacuum to obtain crystalline form (III) of compound (I).

[0181] Example 4: Preparation of Crystalline Form (IV) of Compound (I) Amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile was dissolved in 2-methyl-1-propanol. The solution was filtered and the solvent was slowly evaporated, followed by drying to give a white solid. The dried solid was analyzed. The dried solid was analyzed and found to be crystalline Form (IV) of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0182] Example 5: Preparation of Crystalline Form (V) of Compound (I) Amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile was dissolved in toluene. The solution was filtered and the solvent was slowly evaporated, followed by drying, to give a white solid. The solid was analyzed and identified as crystalline Form (V) of Compound (I).

Claims

1. Compound (I): 【Chemistry 1】 The crystalline form (I) of

2. 2. The crystalline form (I) of claim 1, characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2, and 22.1±0.

2.

3. 2. Crystalline form (I) according to claim 1, characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram shown in Figure 1.

4. Crystalline form (I) according to any one of claims 1 to 3, characterized by a DSC thermogram with a peak endotherm (melting point) at about 177°C to about 178°C.

5. Crystalline form (I) according to any one of claims 1 to 4, characterized by a DSC thermogram showing an onset of melting at about 174.8°C to about 175.2°C.

6. The crystalline form (I) according to any one of claims 1 to 5, wherein at least 95% by weight of compound (I) is the (E) isomer.

7. The crystalline form (I) of any one of claims 1 to 6, wherein at least 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

8. adding methyl isobutyl ketone to amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile to form a solution; agitating the solution to form a precipitate; and Isolating the crystalline form (I) by filtration.

2. A crystalline form (I) of compound (I) prepared by a process comprising:

9. Compound (I): 【Chemistry 2】 The crystalline form (II) of

10. 10. The crystalline form (II) of claim 9, characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.

2.

11. 10. Crystalline form (II) according to claim 9, characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in Figure 3.

12. Crystalline form (II) according to any one of claims 9 to 11, characterized by a DSC thermogram with a peak endotherm (melting point) at about 170.0°C to about 170.2°C.

13. Crystalline form (II) according to any one of claims 9 to 12, characterized by a DSC thermogram showing an onset of melting at about 167.2°C to about 167.6°C.

14. Crystalline form (II) according to any one of claims 9 to 13, characterized by a mass loss by thermogravimetric analysis of less than 1.5% by weight between 35°C and 220°C.

15. Crystalline form (II) according to any one of claims 9 to 14, wherein at least 95% by weight of compound (I) is the (E) isomer.

16. Crystalline form (II) according to any one of claims 9 to 15, wherein at least 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

17. dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl t-butyl ether to form a solution; stirring the solution to form a precipitate; and Isolating crystalline form (II) by filtration.

2. A crystalline form (II) of compound (I), prepared by a process comprising:

18. Compound (I): 【Transformation 3】 The crystalline form (III) of

19. 19. The crystalline form (III) of claim 18, characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 10.3±0.2, 15.1±0.2, 16.5±0.2, 17.6±0.2, 20.0±0.2, and 22.5±0.

2.

20. 19. Crystalline form (III) according to claim 18, characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in Figure 5.

21. Crystalline form (III) according to any one of claims 18 to 20, characterized by a DSC thermogram with a peak endotherm (melting point) at about 167.4°C to about 167.8°C.

22. Crystalline form (III) according to any one of claims 18 to 21, characterized by a DSC thermogram showing an onset of melting at about 165.1°C to about 165.5°C.

23. Crystalline form (III) according to any one of claims 18 to 22, wherein at least 95% by weight of compound (I) is the (E) isomer.

24. Crystalline form (III) according to any one of claims 18 to 23, wherein at least 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

25. Dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl t-butyl ether; and Isolating crystalline form (III) by filtration.

2. A crystalline form (III) of compound (I) prepared by a process comprising:

26. Compound (I): 【Chemistry 4】 The crystalline form (IV) of

27. 27. The crystalline form (IV) of claim 26, characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 4.7±0.2, 6.6±0.2, 6.8±0.2, 13.4±0.2, 13.5±0.2, 20.1±0.2, 20.2±0.2, 20.3±0.2, and 24.2±0.

2.

28. 27. Crystalline form (IV) according to claim 26, characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in Figure 7.

29. Crystalline form (IV) according to any one of claims 26 to 28, characterized by a mass loss by thermogravimetric analysis between 70°C and 180°C of less than 14% by weight.

30. Crystalline form (IV) according to any one of claims 26 to 29, wherein at least 95% by weight of compound (I) is the (E) isomer.

31. 31. The crystalline form (IV) of any one of claims 26 to 30, wherein at least 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

32. dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in 2-methyl-1-propanol to form a solution; filtering the solution; and Isolating the crystalline form (IV) by evaporating the 2-methyl-1-propanol.

2. A crystalline form (IV) of compound (I) prepared by a process comprising:

33. Compound (I): 【Transformation 5】 The crystalline form (V) of

34. 34. The crystalline form (V) of claim 33, characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 4.7±0.2, 6.5±0.2, 14.2±0.2, 16.2±0.2, 16.5±0.2, 19.8±0.2, and 20.7±0.

2.

35. 34. Crystalline form (V) according to claim 33, characterized by an X-ray powder diffractogram substantially similar to the X-ray powder diffractogram in Figure 9.

36. Crystalline form (V) according to any one of claims 33 to 35, characterized by a mass loss by thermogravimetric analysis of less than 7% by weight between 75°C and 110°C.

37. Crystalline form (V) according to any one of claims 33 to 36, wherein at least 95% by weight of compound (I) is the (E) isomer.

38. 38. The crystalline form (V) of any one of claims 33 to 37, wherein at least 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

39. dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in toluene to form a solution; filtering the solution; and Isolating the crystalline form (V) by evaporating the toluene.

2. A crystalline form (V) of compound (I) prepared by a process comprising:

40. at least one pharmaceutically acceptable excipient; and A pharmaceutical composition comprising at least one crystalline form selected from the crystalline forms of any one of claims 1 to 39.

41. 40. A method of inhibiting Bruton's tyrosine kinase (BTK) in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of claims 1 to 39. 。

42. 40. A method of treating a disease mediated by BTK in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of any one of claims 1 to 39.

43. Diseases include pemphigus vulgaris, pemphigus foliaceus, immune thrombocytopenia, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, alopecia areata, vitiligo, pyoderma gangrenosum, pemphigoid membranes, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug eruption, folliculitis barbae, pseudofolliculitis hair folliculitis, 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, scleroderma, Wegener's granulomatosis, psoriasis, asthma, colitis, and conjunctival 43. The method of claim 42, wherein the tumor is selected from inflammation, dermatitis, uveitis, eczema, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell 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.

44. The method of any one of claims 41 to 43, wherein the mammal is a human.

45. adding methyl isobutyl ketone to amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile to form a solution; agitating the solution to form a precipitate; and Isolating the crystalline form (I) by filtration.

1. A process for preparing crystalline form (I) of compound (I), comprising:

46. dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl t-butyl ether to form a solution; stirring the solution to form a precipitate; and Isolating crystalline form (II) by filtration.

1. A process for preparing crystalline form (II) of compound (I), comprising:

47. Dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl t-butyl ether; and Isolating crystalline form (III) by filtration.

1. A process for preparing crystalline form (III) of compound (I), comprising:

48. dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in 2-methyl-1-propanol to form a solution; filtering the solution; and Isolating the crystalline form (IV) by evaporating the 2-methyl-1-propanol.

1. A process for preparing crystalline form (IV) of compound (I), comprising:

49. dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile in toluene to form a solution; filtering the solution; and Isolating the crystalline form (V) by evaporating the toluene.

1. A process for preparing crystalline form (V) of compound (I), comprising:

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