Crystalline forms of bruton tyrosine kinase inhibitor

Abstract

To provide an oral pharmaceutical formulation comprising a Bruton tyrosine kinase (Btk) inhibitor.SOLUTION: Provided is a pharmaceutical formulation comprising (a) about 40 mg to about 200 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; (b) about 40 wt.% to about 50 wt.% of a diluent; (c) about 3 wt.% to about 10 wt.% of a disintegrant; (d) about 2 wt.% to about 7 wt.% of a surfactant; and (e) about 0.2 wt.% to about 1.0 wt.% of a lubricant.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] <Related Applications> This application claims the benefit of U.S. Provisional Patent Application No. 61 / 655,381, entitled "CRYSTALLINE FORMS OF A BRUTON'S TYROSINE KINASE INHIBITOR," filed July 4, 2012, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION Described herein is a Bruton's tyrosine kinase (Btk) inhibitor, 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, including crystalline forms, solvates, and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising the Btk inhibitor, and methods of using the Btk inhibitor in the treatment of diseases or disorders that benefit from inhibition of Btk activity. [Background technology]

[0003] Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays a key role in the B cell signaling pathway, linking cell surface B cell receptor (BCR) stimulation to downstream intracellular responses.

[0004] Btk is a key regulator of B cell development, activation, signaling, and survival. In addition, Btk plays a role in many other hematopoietic cell signaling pathways, such as Toll-like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, inhibition of Fas / APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation.

[0005] 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is also known by its IUPAC name as 1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-one or 2-propen-1-one, 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl-, and has been given the USAN name, ibrutinib. The various names given for ibrutinib are used interchangeably herein. Summary of the Invention

[0006] Described herein is the Btk inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (including pharmaceutically acceptable solvates (including hydrates), polymorphs, and amorphous phases), and methods of use thereof. Also described are pharmaceutically acceptable salts of the Btk inhibitor (including pharmaceutically acceptable solvates (including hydrates), polymorphs, and amorphous phases), and methods of use thereof. 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, as well as pharmaceutically acceptable salts thereof, are used in the manufacture of medicaments for the treatment of diseases or disorders associated with Btk activity. 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is an irreversible Btk inhibitor.

[0007] Also described herein are methods for preparing crystalline forms of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one. Additionally, described are pharmaceutical compositions containing the crystalline forms, as well as methods for using Btk inhibitors in the treatment of diseases or conditions, including diseases or conditions in which irreversible inhibition of Btk provides a therapeutic benefit to a mammal having the disease or condition.

[0008] In one embodiment, anhydrous 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is described.

[0009] In another embodiment, anhydrous crystalline 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is described.

[0010] In a further embodiment, anhydrous amorphous 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is described.

[0011] In one embodiment, solvates of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are described.

[0012] In one embodiment, solvates are described wherein 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is solvated with methyl isobutyl ketone (MIBK), toluene, or methanol. In one embodiment, solvates are described wherein 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is solvated with methyl isobutyl ketone (MIBK) or toluene. In one embodiment, a solvate is described wherein 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is solvated with methanol.

[0013] In a further embodiment, the solvate is anhydrous.

[0014] In another embodiment, the solvate is crystalline.

[0015] In yet another embodiment, the solvate is amorphous.

[0016] In one embodiment, described herein is crystalline Form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 1 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.7 ± 0.1° 2-theta, 13.6 ± 0.1° 2-theta, 16.1 ± 0.1° 2-theta, 18.9 ± 0.1° 2-theta, 21.3 ± 0.1° 2-theta, and 21.6 ± 0.1° 2-theta; (c) Nearly identical X-ray powder diffraction (XRPD) patterns after storage at 40°C and 75% RH for at least one week; (d) Nearly identical X-ray powder diffraction (XRPD) patterns after storage at 25°C and 97% RH for at least one week; (e) Infrared (IR) spectrum, roughly similar to that shown in Figure 2 ; (f) Approximately 1584cm -1 , approx. 1240cm -1 , approx. 1147cm -1 , approx. 1134cm -1 , approximately 1099 cm -1 , and approximately 1067 cm -1 A weak peak in the infrared (IR) spectrum at ; (g) DSC thermogram roughly similar to that shown in Figure 3 ; (h) Thermogravimetric analysis (TGA) thermogram roughly similar to that shown in Figure 4 ; (i) a DSC thermogram with an endotherm with an onset at about 154°C and a peak at about 157°C, and an exotherm at about 159°C; (j) non-hygroscopic; (k) an observed aqueous solubility of about 0.013 mg / mL at about pH 8; Or, (n) A combination thereof.

[0017] In some embodiments, crystalline form A has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 1. In some embodiments, crystalline form A has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.7±0.1°2-theta, 13.6±0.1°2-theta, 16.1±0.1°2-theta, 18.9±0.1°2-theta, 21.3±0.1°2-theta, and 21.6±0.1°2-theta. In some embodiments, crystalline form A has substantially the same X-ray powder diffraction (XRPD) pattern after storage at 40°C and 75% RH for at least one week. In some embodiments, crystalline form A has substantially the same X-ray powder diffraction (XRPD) pattern after storage at 25°C and 97% RH for at least one week. In some embodiments, crystalline form A has an infrared (IR) spectrum substantially similar to that shown in Figure 2. In some embodiments, crystalline form A has a molecular weight of about 1584 cm -1 , approx. 1240cm -1 , approx. 1147cm -1 , approx. 1134cm -1 , approximately 1099 cm -1 , and approximately 1067 cm -1In some embodiments, crystalline form A has a weak peak in the infrared (IR) spectrum at about 155-156°C. In some embodiments, crystalline form A has a DSC thermogram substantially similar to that shown in Figure 3. In some embodiments, crystalline form A has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 4. In some embodiments, crystalline form A has a DSC thermogram with an endotherm with an onset at about 154°C and a peak at about 157°C, and an exotherm at about 159°C. In some embodiments, crystalline form A is non-hygroscopic. In some embodiments, crystalline form A has an observed aqueous solubility of about 0.013 mg / mL at about pH 8. In some embodiments, crystalline form A is characterized as having properties (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), and (k). In some embodiments, crystalline Form A was obtained from ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole, acetone, heptane, a methanol / water mixture, or an acetone / heptane mixture. In some embodiments, crystalline Form A was obtained from a methanol / water mixture. In some embodiments, crystalline Form A is unsolvated. In some embodiments, crystalline Form A is anhydrous.

[0018] In one embodiment, described herein is crystalline Form B of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 5 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.2 ± 0.1° 2-theta, 10.2 ± 0.1° 2-theta, 16.5 ± 0.1° 2-theta, 18.5 ± 0.1° 2-theta, and 20.8 ± 0.1° 2-theta; (c) Nearly identical X-ray powder diffraction (XRPD) patterns after storage at 40°C and 75% RH for at least 1 week; (d) Nearly identical X-ray powder diffraction (XRPD) patterns after storage at 25°C and 97% RH for at least one week; (e) Infrared (IR) spectrum, roughly similar to that shown in Figure 6 ; (f) Approximately 1586cm -1 , approx. 1573cm -1 , approx. 1562cm -1 , approx. 1229cm -1 , approx. 1141cm -1 , approx. 1103cm -1 , approximately 1056 cm -1 , and approximately 1033 cm -1 A weak peak in the infrared (IR) spectrum at ; (g) DSC thermogram roughly similar to that shown in Figure 7 ; (h) Thermogravimetric analysis (TGA) thermogram roughly similar to that shown in Figure 8 ; (i) a DSC thermogram with an endotherm with an onset at about 99-106°C and a peak at about 115-118°C; (j) an observed aqueous solubility of about 0.0096 mg / mL at about pH 7.42; Or, (k) Combinations thereof.

[0019] In some embodiments, crystalline form B has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 5. In some embodiments, crystalline form B has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.2±0.1°2-theta, 10.2±0.1°2-theta, 16.5±0.1°2-theta, 18.5±0.1°2-theta, and 20.8±0.1°2-theta. In some embodiments, crystalline form B has substantially the same X-ray powder diffraction (XRPD) pattern after storage at 40°C and 75% RH for at least one week. In some embodiments, crystalline form B has substantially the same X-ray powder diffraction (XRPD) pattern after storage at 25°C and 97% RH for at least one week. In some embodiments, crystalline form B has an infrared (IR) spectrum substantially similar to that shown in Figure 6. In some embodiments, crystalline form B has a peak at 1586 cm -1 , approx. 1573cm -1 , approx. 1562cm -1 , approx. 1229cm -1 , approx. 1141cm -1 , approx. 1103cm -1 , approximately 1056 cm -1 , and approximately 1033 cm -1In some embodiments, crystalline form B has a weak peak in the infrared (IR) spectrum at 10°C. In some embodiments, crystalline form B has a DSC thermogram substantially similar to that shown in Figure 7. In some embodiments, crystalline form B has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 8. In some embodiments, crystalline form B has a DSC thermogram with an endotherm with an onset at about 99-106°C and a peak at about 115-118°C. In some embodiments, crystalline form B has an observed aqueous solubility of about 0.0096 mg / mL at a pH of about 7.42. In some embodiments, crystalline form B is characterized as having properties (a), (b), (c), (d), (e), (f), (g), (h), (i), and (j). In some embodiments, crystalline form B was obtained from a mixture of methanol and water. In some embodiments, crystalline form B is unsolvated. In some embodiments, crystalline form B is anhydrous.

[0020] In one embodiment, described herein is crystalline form C of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 9 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0 ± 0.1° 2-theta, 14.0 ± 0.1° 2-theta, 15.7 ± 0.1° 2-theta, 18.2 ± 0.1° 2-theta, 19.1 ± 0.1° 2-theta, 19.5 ± 0.1° 2-theta, 20.3 ± 0.1° 2-theta, 22.1 ± 0.1° 2-theta, and 22.9 ± 0.1° 2-theta; (c) DSC thermogram roughly similar to that shown in Figure 10 ; (d) Thermogravimetric analysis (TGA) thermogram roughly similar to that shown in Figure 11 ; (e) DSC thermogram with an endotherm with an onset at about 99-106°C and a peak at about 115-118°C; Or, (f) combinations thereof.

[0021] In some embodiments, crystalline form C has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 9. In some embodiments, crystalline form C has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0±0.1°2-theta, 14.0±0.1°2-theta, 15.7±0.1°2-theta, 18.2±0.1°2-theta, 19.1±0.1°2-theta, 19.5±0.1°2-theta, 20.3±0.1°2-theta, 22.1±0.1°2-theta, and 22.9±0.1°2-theta. In some embodiments, crystalline form C has a DSC thermogram substantially similar to that shown in Figure 10. In some embodiments, crystalline form C has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 11. In some embodiments, crystalline form C has a DSC thermogram with an endotherm with an onset at about 134-135°C and a peak at about 137-139°C. In some embodiments, crystalline form C is characterized as having properties (a), (b), (c), (d), and (e). In some embodiments, crystalline form C was obtained from a mixture of methanol and water. In some embodiments, crystalline form C is unsolvated. In some embodiments, crystalline form C is anhydrous.

[0022] In one embodiment, described herein is crystalline form D of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 12 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.2 ± 0.1° 2-theta, 8.0 ± 0.1° 2-theta, 9.2 ± 0.1° 2-theta, 14.5 ± 0.1° 2-theta, 18.5 ± 0.1° 2-theta, 19.5 ± 0.1° 2-theta, 20.7 ± 0.1° 2-theta, 21.0 ± 0.1° 2-theta, 21.9 ± 0.1° 2-theta, and 22.4 ± 0.1° 2-theta; (c) Thermogravimetric analysis (TGA) thermogram roughly similar to that shown in Figure 13 ; Or, (d) combinations thereof.

[0023] In some embodiments, crystalline form D has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 12. In some embodiments, crystalline form D has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.2±0.1°2-theta, 8.0±0.1°2-theta, 9.2±0.1°2-theta, 14.5±0.1°2-theta, 18.5±0.1°2-theta, 19.5±0.1°2-theta, 20.7±0.1°2-theta, 21.0±0.1°2-theta, 21.9±0.1°2-theta, and 22.4±0.1°2-theta. In some embodiments, crystalline form D has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 13. In some embodiments, crystalline form D is characterized as having properties (a), (b), and (c). In some embodiments, crystalline form D was obtained from methyl isobutyl ketone (MIBK). In some embodiments, crystalline form D is solvated. In some embodiments, crystalline form D is solvated with methyl isobutyl ketone (MIBK).

[0024] In one embodiment, described herein is crystalline form E of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 14 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.8 ± 0.1° 2-theta, 8.8 ± 0.1° 2-theta, 16.1 ± 0.1° 2-theta, 18.1 ± 0.1° 2-theta, 19.3 ± 0.1° 2-theta, 19.5 ± 0.1° 2-theta, 20.5 ± 0.1° 2-theta, 21.6 ± 0.1° 2-theta, and 25.2 ± 0.1° 2-theta; (c) DSC thermogram roughly similar to that shown in Figure 15 ; (d) Thermogravimetric analysis (TGA) thermogram roughly similar to that shown in Figure 15 ; Or, (e) combinations thereof.

[0025] In some embodiments, crystalline form E has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 14. In some embodiments, crystalline form E has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.8±0.1°2-theta, 8.8±0.1°2-theta, 16.1±0.1°2-theta, 18.1±0.1°2-theta, 19.3±0.1°2-theta, 19.5±0.1°2-theta, 20.5±0.1°2-theta, 21.6±0.1°2-theta, and 25.2±0.1°2-theta. In some embodiments, crystalline form E has a DSC thermogram substantially similar to that shown in Figure 15. In some embodiments, crystalline form E has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 15. In some embodiments, crystalline form E is characterized as having properties (a), (b), (c), and (d). In some embodiments, crystalline form A was obtained from toluene. In some embodiments, crystalline form E is solvated. In some embodiments, crystalline form E is solvated with toluene.

[0026] In one embodiment, described herein is crystalline form F of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 16 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.2±0.1°2-theta, 10.1±0.1°2-theta, 17.6±0.1°2-theta, 18.6±0.1°2-theta, 20.0±0.1°2-theta, 20.4±0.1°2-theta, 20.7±0.1°2-theta, 22.4±0.1°2-theta, 23.0±0.1°2-theta, 23.2±0.1°2-theta, 24.4±0.1°2-theta, 25.1±0.1°2-theta, 27.6±0.1°2-theta, and 29.3±0.1°2-theta; (c) Unit cell parameters at 100(2) K approximately equal to:

[0027] [Table 1]

[0028] Or, (d) combinations thereof.

[0029] In some embodiments, crystalline form F has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. In some embodiments, crystalline form F has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.2±0.1°2-theta, 10.1±0.1°2-theta, 17.6±0.1°2-theta, 18.6±0.1°2-theta, 20.0±0.1°2-theta, 20.4±0.1°2-theta, 20.7±0.1°2-theta, 22.4±0.1°2-theta, 23.0±0.1°2-theta, 23.2±0.1°2-theta, 24.4±0.1°2-theta, 25.1±0.1°2-theta, 27.6±0.1°2-theta, and 29.3±0.1°2-theta.

[0030] In some embodiments, crystalline form F has unit cell parameters at 100(2) K approximately equal to:

[0031] [Table 2]

[0032] In some embodiments, crystalline form F was obtained from methanol.

[0033] In some embodiments, crystalline form F is solvated. In some embodiments, crystalline form F is solvated with methanol.

[0034] In one aspect, described herein is a pharmaceutically acceptable salt of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, wherein the pharmaceutically acceptable salt is an acid addition salt. In some embodiments, the pharmaceutically acceptable salt is amorphous. In some embodiments, the pharmaceutically acceptable salt is crystalline.

[0035] In a further aspect, provided are pharmaceutical compositions comprising 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-ylprop-2-en-1-one, as described herein, and at least one additional ingredient selected from a pharmaceutically acceptable carrier, diluent, and excipient. In some embodiments, the pharmaceutical composition comprises Form A. In some embodiments, the pharmaceutical composition comprises Form B. In some embodiments, the pharmaceutical composition comprises Form C. In some embodiments, the pharmaceutical composition comprises Form D. In some embodiments, the pharmaceutical composition comprises Form E. In some embodiments, the pharmaceutical composition comprises Form F. In some embodiments, the pharmaceutical composition is in a form suitable for oral administration to a mammal. In some embodiments, the pharmaceutical composition is an oral solid dosage form.

[0036] In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 1000 mg of crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.

[0037] In another aspect, provided herein is a pharmaceutical formulation for oral administration comprising:

[0038] (a) about 40 mg to about 200 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0039] (b) about 40 wt % to about 50 wt % diluent;

[0040] (c) about 3 wt% to about 10 wt% of a disintegrant;

[0041] (d) about 2 wt % to about 7 wt % of a surfactant; and

[0042] (e) about 0.2 wt % to about 1.0 wt % of a lubricant.

[0043] In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcrystalline cellulose, and talc. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the disintegrant is selected from the group consisting of native starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked starches such as cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, and copolymers of ethylene oxide and propylene oxide. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax. In some embodiments, the lubricant is magnesium stearate.

[0044] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0045] (a) about 40 mg to about 200 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0046] (b) about 40 wt % to about 50 wt % microcrystalline cellulose;

[0047] (c) about 3 wt% to about 10 wt% croscarmellose sodium;

[0048] (d) about 2 wt % to about 7 wt % sodium lauryl sulfate; and

[0049] (e) about 0.2 wt % to about 1.0 wt % magnesium stearate.

[0050] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0051] (a) about 40 wt % to about 50 wt % of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0052] (b) about 40 wt % to about 50 wt % microcrystalline cellulose;

[0053] (c) about 3 wt% to about 10 wt% croscarmellose sodium;

[0054] (d) about 2 wt % to about 7 wt % sodium lauryl sulfate; and

[0055] (e) about 0.2 wt % to about 1.0 wt % magnesium stearate.

[0056] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0057] (a) 140 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0058] (b) 45.9 wt% microcrystalline cellulose;

[0059] (c) 7.0 wt% croscarmellose sodium;

[0060] (d) 4.2 wt. % sodium lauryl sulfate; and

[0061] (e) 0.5 wt% magnesium stearate.

[0062] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0063] (a) 140 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0064] (b) 151.4 mg microcrystalline cellulose;

[0065] (c) 23.0 mg croscarmellose sodium;

[0066] (d) 14.0 mg sodium lauryl sulfate; and

[0067] (e) 1.6 mg magnesium stearate.

[0068] In another aspect, provided herein is a pharmaceutical formulation for oral administration comprising:

[0069] (a) about 40 mg to about 200 mg of crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0070] (b) about 40 wt % to about 50 wt % diluent;

[0071] (c) about 3 wt% to about 10 wt% of a disintegrant;

[0072] (d) about 2 wt % to about 7 wt % of a surfactant; and

[0073] (e) about 0.2 wt % to about 1.0 wt % of a lubricant.

[0074] In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcrystalline cellulose, and talc. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the disintegrant is selected from the group consisting of native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked starches such as cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, and copolymers of ethylene oxide and propylene oxide. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax. In some embodiments, the lubricant is magnesium stearate.

[0075] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0076] (a) about 40 mg to about 200 mg of crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0077] (b) about 40 wt % to about 50 wt % microcrystalline cellulose;

[0078] (c) about 3 wt% to about 10 wt% croscarmellose sodium;

[0079] (d) about 2 wt % to about 7 wt % sodium lauryl sulfate; and

[0080] (e) about 0.2 wt % to about 1.0 wt % magnesium stearate.

[0081] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0082] (a) about 40 wt % to about 50 wt % crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0083] (b) about 40 wt % to about 50 wt % microcrystalline cellulose;

[0084] (c) about 3 wt% to about 10 wt% croscarmellose sodium;

[0085] (d) about 2 wt % to about 7 wt % sodium lauryl sulfate; and

[0086] (e) about 0.2 wt % to about 1.0 wt % magnesium stearate.

[0087] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0088] (a) 140 mg of crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0089] (b) 45.9 wt% microcrystalline cellulose;

[0090] (c) 7.0 wt% croscarmellose sodium;

[0091] (d) 4.2 wt. % sodium lauryl sulfate; and

[0092] (e) 0.5 wt% magnesium stearate.

[0093] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0094] (a) 140 mg of crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0095] (b) 151.4 mg microcrystalline cellulose;

[0096] (c) 23.0 mg croscarmellose sodium;

[0097] (d) 14.0 mg sodium lauryl sulfate; and

[0098] (e) 1.6 mg magnesium stearate.

[0099] In some embodiments of the aforementioned pharmaceutical formulations, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are crystalline form A. In some embodiments of the aforementioned pharmaceutical formulations, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are crystalline form B. In some embodiments of the aforementioned pharmaceutical formulations, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are crystalline form C. In some embodiments of the aforementioned pharmaceutical formulations, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are crystalline form D. In some embodiments of the aforementioned pharmaceutical formulations, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are crystalline form E. In some embodiments of the aforementioned pharmaceutical formulations, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are crystalline form F. In some embodiments of the aforementioned pharmaceutical formulation embodiments, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are a mixture of two or more crystalline forms selected from the group consisting of Form A, Form B, Form C, Form D, Form E, and Form F. In another embodiment of the aforementioned pharmaceutical formulation embodiments, provided herein is a pharmaceutical formulation, wherein the dosage form is a hard gelatin capsule.

[0100] In another aspect, provided herein is a pharmaceutical formulation for oral administration comprising:

[0101] (a) about 40 mg to about 200 mg of crystalline Form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0102] (b) about 40 wt % to about 50 wt % diluent;

[0103] (c) about 3 wt% to about 10 wt% of a disintegrant;

[0104] (d) about 2 wt % to about 7 wt % of a surfactant; and

[0105] (e) about 0.2 wt % to about 1.0 wt % of a lubricant.

[0106] In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcrystalline cellulose, and talc. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the disintegrant is selected from the group consisting of native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked starch such as cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, and copolymers of ethylene oxide and propylene oxide. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax. In some embodiments, the lubricant is magnesium stearate.

[0107] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0108] (a) about 40 mg to about 200 mg of crystalline Form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0109] (b) about 40 wt % to about 50 wt % microcrystalline cellulose;

[0110] (c) about 3 wt% to about 10 wt% croscarmellose sodium;

[0111] (d) about 2 wt % to about 7 wt % sodium lauryl sulfate; and

[0112] (e) about 0.2 wt % to about 1.0 wt % magnesium stearate.

[0113] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0114] (a) about 40 wt % to about 50 wt % crystalline Form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0115] (b) about 40 wt % to about 50 wt % microcrystalline cellulose;

[0116] (c) about 3 wt% to about 10 wt% croscarmellose sodium;

[0117] (d) about 2 wt % to about 7 wt % sodium lauryl sulfate; and

[0118] (e) about 0.2 wt % to about 1.0 wt % magnesium stearate.

[0119] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0120] (a) 140 mg of crystalline form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0121] (b) 45.9 wt% microcrystalline cellulose;

[0122] (c) 7.0 wt% croscarmellose sodium;

[0123] (d) 4.2 wt. % sodium lauryl sulfate; and

[0124] (e) 0.5 wt% magnesium stearate.

[0125] In some embodiments, provided herein is a pharmaceutical formulation for oral administration comprising:

[0126] (a) 140 mg of crystalline form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0127] (b) 151.4 mg microcrystalline cellulose;

[0128] (c) 23.0 mg croscarmellose sodium;

[0129] (d) 14.0 mg sodium lauryl sulfate; and

[0130] (e) 1.6 mg magnesium stearate.

[0131] In another aspect, provided herein is a pharmaceutical formulation comprising: a) about 40 mg to about 200 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; b) about 40 wt % to about 50 wt % of a diluent; c) about 3 wt % to about 10 wt % of a disintegrant; d) about 2 wt % to about 7 wt % of a surfactant; and e) about 0.2 wt % to about 1.0 wt % of a lubricant; wherein the formulation is in unit dosage form in a blister pack, and the blister pack comprises a metal or plastic foil. In some embodiments, the pharmaceutical formulation comprises: a) 140 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; b) 45.9 wt% microcrystalline cellulose; c) 7.0 wt% croscarmellose sodium; d) 4.2 wt% sodium lauryl sulfate; and e) about 0.5 wt% magnesium stearate, wherein the formulation is in unit dosage form in a blister pack, and the blister pack comprises metal or plastic foil.

[0132] In another embodiment, a package comprising one or more separate blister pockets is described, wherein each blister pocket contains a unit dosage form comprising: a) about 40 mg to about 200 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; b) about 40 wt% to about 50 wt% of a diluent; c) about 3 wt% to about 10 wt% of a disintegrant; d) about 2 wt% to about 7 wt% of a surfactant; and e) about 0.2 wt% to about 1.0 wt% of a lubricant; wherein each blister pocket comprises a metal or plastic foil.

[0133] In another aspect, provided herein is a pharmaceutical formulation comprising: a) about 40 mg to about 200 mg of crystalline Form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; b) about 40 wt % to about 50 wt % of a diluent; c) about 3 wt % to about 10 wt % of a disintegrant; d) about 2 wt % to about 7 wt % of a surfactant; and e) about 0.2 wt % to about 1.0 wt % of a lubricant; wherein the formulation is in unit dosage form in a blister pack, and the blister pack comprises a metal or plastic foil. In some embodiments, the pharmaceutical formulation comprises: a) 140 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; b) 45.9 wt% microcrystalline cellulose; c) 7.0 wt% croscarmellose sodium; d) 4.2 wt% sodium lauryl sulfate; and e) about 0.5 wt% magnesium stearate, wherein the formulation is in unit dosage form in a blister pack, and the blister pack comprises metal or plastic foil.

[0134] In another embodiment, a package comprising one or more separate blister pockets is described, wherein each blister pocket contains a unit dosage form comprising: a) about 40 mg to about 200 mg of crystalline Form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; b) about 40 wt% to about 50 wt% of a diluent; c) about 3 wt% to about 10 wt% of a disintegrant; d) about 2 wt% to about 7 wt% of a surfactant; and e) about 0.2 wt% to about 1.0 wt% of a lubricant; wherein each blister pocket comprises a metal or plastic foil.

[0135] In one embodiment, a kit is provided that includes multiple oral dosage forms, such as tablets or capsules, a package, such as a bottle, containing the oral dosage forms, and instructions for use to administer the oral dosage forms according to the methods described herein. Unit-dose packages, such as blister packs, provide a useful way to package oral dosage forms of the formulations described herein and, in other embodiments, comprise a kit when combined with instructions for use. In other embodiments, detailed product information is included with the instructions in the kit. Blister packs are particularly useful with solid oral dosage forms, and in further embodiments, are useful for, for example, alternate-day administration. In one embodiment, solid unit dosage forms of the formulations described herein are included in a blister pack with instructions for administering one or more tablets or capsules on a daily basis to provide a sufficient dose of the formulations described herein. In another embodiment, the solid unit dosage forms are included in a blister pack with instructions for administering one or more tablets or capsules on an alternate-day basis to provide a sufficient daily dose.

[0136] In one aspect, provided herein are methods of treating a patient by administering Compound 1. In some embodiments, provided herein are methods of treating a disease, disorder, or condition that would benefit from inhibition of the activity of a tyrosine kinase, such as Btk, or inhibition of a tyrosine kinase, such as Btk, in a mammal, the method comprising administering to the mammal a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate.

[0137] In another aspect, provided herein is the use of Compound 1 for inhibiting Bruton's tyrosine kinase (Btk) activity or for treating a disease, disorder, or condition that would benefit from the inhibition of Bruton's tyrosine kinase (Btk) activity.

[0138] In some embodiments, crystalline Compound 1 is administered to a human.

[0139] In some embodiments, crystalline Compound 1 is administered orally.

[0140] In other embodiments, crystalline Compound 1 is used in the formulation of a medicament for the inhibition of tyrosine kinase activity. In some other embodiments, crystalline Compound 1 is used in the formulation of a medicament for the inhibition of Bruton's tyrosine kinase (Btk) activity.

[0141] In one aspect, provided herein is a method of treating cancer in a mammal, comprising administering to the mammal a pharmaceutical composition described herein comprising Compound 1. In some embodiments, the cancer is a B-cell malignancy. In some embodiments, the cancer is a B-cell malignancy selected from chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma. In some embodiments, the cancer is a lymphoma, leukemia, or solid tumor. In some embodiments, the cancer is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Wandelstrom 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, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis. In some embodiments, if the subject is suffering from cancer, an anti-cancer agent is administered to the subject in addition to one of the aforementioned compounds. In one embodiment, the anti-cancer agent is an inhibitor of mitogenic protein kinase signaling.

[0142] In one aspect, provided herein is a method of treating an inflammatory or autoimmune disease in a mammal, comprising administering to the mammal a pharmaceutical composition described herein comprising Compound 1. In some embodiments, the inflammatory disease is selected from the group consisting of asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymal palsy, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, and the like. Laryngitis, mastitis, meningitis, myelitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, interstitial pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, eustachian tube inflammation, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginal inflammation, vasculitis, or vulvitis. In some embodiments, the autoimmune disease is inflammatory bowel disease, arthritis, autoimmune diseases, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile rheumatoid arthritis, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus ataxia, ankylosing spondylitis, antiphospholipids, anti-inflammatory drugs ... Lipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic neuropathy, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.

[0143] An article of manufacture is provided that includes packaging material, Compound 1 within the packaging material, and a label that indicates Compound 1 is used for inhibiting the activity of a tyrosine kinase, such as Btk.

[0144] In a further aspect, provided herein is a method of treating an autoimmune disease in a mammal, comprising administering Compound 1 to the mammal.

[0145] In a further aspect, provided herein is a method of treating a heteroimmune disease or disorder in a mammal, comprising administering Compound 1 to the mammal.

[0146] In a further aspect, provided herein is a method of treating an inflammatory disease in a mammal, comprising administering Compound 1 to the mammal.

[0147] In a further aspect, provided herein is a method of treating cancer in a mammal, comprising administering Compound 1 to the mammal.

[0148] In a further aspect, provided herein is a method of treating a thromboembolic disorder in a mammal, comprising administering to the mammal Compound 1. Thromboembolic disorders include, but are not limited to, myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, or deep vein thrombosis.

[0149] In another embodiment, a method of modulating is provided that includes irreversibly inhibiting the activity of Btk or other tyrosine kinases in a mammal, wherein the other tyrosine kinases share homology with Btk by having a cysteine ​​residue (including Cys481 residue) that can form a covalent bond with Compound 1, the method comprising administering to the mammal at least one effective amount of Compound 1. In another embodiment, a method of modulating is provided that includes irreversibly inhibiting the activity of Btk in a mammal, the method comprising administering to the mammal at least one effective amount of Compound 1. In another embodiment, a method is provided for treating a Btk-dependent or Btk-mediated disease or disorder, the method comprising administering to the mammal at least one effective amount of Compound 1.

[0150] In another embodiment, a method for treating inflammation is provided, comprising administering an effective amount of Compound 1 to a mammal at least once.

[0151] In a further aspect, there is provided a method for treating cancer, comprising administering to a mammal at least once an effective amount of Compound 1. The types of cancer include, but are not limited to, pancreatic cancer and other solid or hematological tumors.

[0152] In another aspect, a method for treating a respiratory disease is provided, comprising administering at least one effective amount of Compound 1 to a mammal. In a further embodiment of this aspect, the respiratory disease is asthma. In a further embodiment of this aspect, respiratory diseases include, but are not limited to, adult respiratory distress syndrome, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-type asthma, occupational asthma, steroid-refractory asthma, and seasonal asthma.

[0153] In another aspect, a method for preventing rheumatoid arthritis and / or osteoarthritis is provided, comprising administering an effective amount of Compound 1 to a mammal at least once.

[0154] In another aspect, there is provided a method for treating inflammatory skin reactions, comprising administering to a mammal at least once an effective amount of Compound 1. Such inflammatory skin reactions include, by way of example only, dermatitis, contact dermatitis, eczema, hives, rosacea, and scarring. In another aspect, there is provided a method for reducing psoriatic lesions in the skin, joints, or other tissues or organs, comprising administering to a mammal at least once an effective amount of Compound 1.

[0155] In another aspect, there is provided the use of Compound 1 in the manufacture of a medicament for the treatment of an inflammatory disease or condition in an animal in which the activity of Btk or other tyrosine kinase contributes to the pathology and / or symptoms of the disease or condition, wherein the other tyrosine kinase shares homology with Btk by possessing a cysteine ​​residue (including the Cys481 residue) capable of forming a covalent bond with at least one irreversible inhibitor described herein. In one embodiment of this aspect, the tyrosine kinase protein is Btk. In another or further aspect of this aspect, the inflammatory disease or condition is a respiratory disease, a cardiovascular disease, or a proliferative disease.

[0156] In any of the above aspects, further embodiments are provided in which Compound 1 is (a) administered systemically to a mammal; (b) administered orally to a mammal; (c) administered intravenously to a mammal; (d) administered by inhalation; (e) administered intranasally; or (f) administered by injection to a mammal; (g) administered topically (transdermally) to a mammal; (h) administered by eye drops; or (i) administered rectally to a mammal.

[0157] In any of the foregoing aspects, further embodiments are provided that include a single administration of Compound 1, including further embodiments in which Compound 1 is administered: (i) once; (ii) multiple times over a daily period; (iii) frequently; or (iv) continuously.

[0158] In any of the foregoing aspects, further embodiments are provided that include multiple administrations of Compound 1, including further embodiments where: (i) Compound 1 is administered in a single dose; (ii) the interval between multiple administrations is every 6 hours; and (iii) Compound 1 is administered to the mammal every 8 hours. In further or alternative embodiments, the method includes a drug holiday, in which administration of Compound 1 is temporarily suspended or the dosage of Compound 1 is temporarily reduced; at the end of the drug holiday, administration of Compound 1 is resumed. The length of the drug holiday can vary from two days to one year.

[0159] In some embodiments, in any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is optically pure (i.e., greater than 99% chiral purity by HPLC). In some embodiments, in any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is replaced with a) Compound 1 of low chiral purity, or a pharmaceutically acceptable salt or solvate thereof; b) 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one of any optical purity, or a pharmaceutically acceptable salt or solvate thereof; or c) 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt or solvate thereof.

[0160] In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), amorphous Compound 1 is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound 1 is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound 1 (Form A) is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound 1 (Form B) is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound 1 (Form C) is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound 1 (Form D) is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound 1 (Form E) is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound 1 (Form F) is used.

[0161] In some embodiments, in any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), Compound 1, or a pharmaceutically acceptable salt thereof, is replaced with an active metabolite of Compound 1. In some embodiments, the active metabolite is in a crystalline form. In some embodiments, the active metabolite is in an amorphous phase. In further embodiments, the metabolite is isolated. In some embodiments, in any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.), Compound 1, or a pharmaceutically acceptable salt thereof, is replaced with a prodrug of Compound 1, or a deuterated analog of Compound 1, or a pharmaceutically acceptable salt thereof.

[0162] Other objects, features, and advantages of the methods and compositions described herein will become apparent from the detailed description that follows. It should be understood, however, that the detailed description and specific examples, while indicating particular embodiments, are given for illustrative purposes only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, including, but not limited to, patents, patent applications, papers, books, manuals, and articles, are expressly incorporated herein by reference in their entirety for any purpose.

[0163] <incorporation by reference> All publications and patent applications mentioned in this specification are herein incorporated by reference to the extent applicable and relevant. [Brief explanation of the drawings]

[0164] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of Form A. [Figure 2] 1 shows the infrared (IR) spectrum of Form A. [Figure 3] 1 shows a DSC thermogram of Form A. [Figure 4]1 shows a thermogravimetric analysis (TGA) thermogram of Form A. [Figure 5] 1 shows the X-ray powder diffraction (XRPD) pattern of Form B. [Figure 6] 1 shows the infrared (IR) spectrum of Form B. [Figure 7] 1 shows a DSC thermogram of Form B. [Figure 8] 1 shows a thermogravimetric analysis (TGA) thermogram of Form B. [Figure 9] 1 shows the X-ray powder diffraction (XRPD) pattern of Form C. [Figure 10] 1 shows a DSC thermogram of Form C. [Figure 11] 1 shows a thermogravimetric analysis (TGA) thermogram of Form C. [Figure 12] 1 shows the X-ray powder diffraction (XRPD) pattern of Form D. [Figure 13] 1 shows a thermogravimetric analysis (TGA) thermogram of Form D. [Figure 14] 1 shows the X-ray powder diffraction (XRPD) pattern of Form E. [Figure 15] 1 shows the DSC thermogram and thermogravimetric analysis (TGA) thermogram of Form E. [Figure 16] 1 shows a simulated X-ray powder diffraction (XRPD) pattern of Form F. DETAILED DESCRIPTION OF THE INVENTION

[0165] The diverse roles played by Btk signaling in various hematopoietic cell functions (e.g., B cell receptor activation) suggest that small molecule Btk inhibitors such as Compound 1 may be useful in reducing the risk of or treating a variety of diseases that are affected by or affect many cells of the hematopoietic lineage, such as autoimmune diseases, alloimmune diseases or disorders, inflammatory diseases, cancers (e.g., B cell proliferative disorders), and thromboembolic disorders. Furthermore, irreversible Btk inhibitor compounds such as Compound 1 can be used to inhibit a small subset of other tyrosine kinases that share homology with Btk by possessing cysteine ​​residues (including cysteine ​​481) that can form covalent bonds with irreversible inhibitors.

[0166] In some embodiments, Compound 1 may be used to treat autoimmune diseases in a mammal, including, but not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile rheumatoid arthritis, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus ataxia, Ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia.

[0167] In some embodiments, Compound 1 may be used in the treatment of a heteroimmune disease or condition in a mammal, including, but not limited to, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy (e.g., allergy to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0168] In some embodiments, Compound 1 may be used in the treatment of inflammatory diseases in a mammal, including, but not limited to, asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymal palsy, fasciitis, These include fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, interstitial pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, eustachian tube inflammation, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginal inflammation, vasculitis, and vulvitis.

[0169] In still other embodiments, the methods described herein may be used to treat cancer, e.g., a B-cell proliferative disorder, including, but not limited to, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Wandelstrom 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, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, and lymphomatoid granulomatosis.

[0170] In further embodiments, the methods described herein may be used to treat thromboembolic disorders, including, but not limited to, myocardial infarction, angina (including unstable angina), re-occlusion or restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, and deep vein thrombosis.

[0171] <Hematologic malignancies> Disclosed herein, in certain embodiments, is a method of treating a hematological malignancy in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1.

[0172] In some embodiments, the hematological malignancy is non-Hodgkin's lymphoma (NHL). In some embodiments, the hematological malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma (MM), marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's high-grade B-cell lymphoma, or extranodal marginal zone B-cell lymphoma. In some embodiments, the hematological malignancy is acute or chronic myeloid (or myeloid) leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, or B-cell precursor acute lymphocytic leukemia. In some embodiments, the hematological malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, the hematological malignancy is mantle cell lymphoma (MCL). In some embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is the ABC subtype of diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is the GCB subtype of diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematological malignancy is chronic lymphocytic leukemia myeloma (MM). In some embodiments, the hematological malignancy is Burkitt's lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma (FL). In some embodiments, the hematological malignancy is transformed follicular lymphoma. In some embodiments, the hematological malignancy is marginal zone lymphoma.

[0173] In some embodiments, the hematological malignancy is relapsed or refractory non-Hodgkin's lymphoma (NHL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma (MCL), relapsed or refractory follicular lymphoma (FL), relapsed or refractory CLL, relapsed or refractory SLL, relapsed or refractory multiple myeloma, relapsed or refractory Waldenstrom's macroglobulinemia, relapsed or refractory multiple myeloma (MM), relapsed or refractory marginal zone lymphoma, relapsed or refractory Burkitt's lymphoma, relapsed or refractory non-Burkitt's high-grade B-cell lymphoma, or relapsed or refractory extranodal marginal zone B-cell lymphoma. In some embodiments, the hematological malignancy is relapsed or refractory acute or chronic myeloid (or myeloid) leukemia, relapsed or refractory myelodysplastic syndrome, relapsed or refractory acute lymphoblastic leukemia, or relapsed or refractory B-cell precursor acute lymphoblastic leukemia. In some embodiments, the hematological malignancy is relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the hematological malignancy is relapsed or refractory mantle cell lymphoma (MCL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some embodiments, the hematological malignancy is relapsed or refractory Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematological malignancy is relapsed or refractory chronic lymphocytic leukemia myeloma (MM). In some embodiments, the hematological malignancy is relapsed or refractory Burkitt's lymphoma. In some embodiments, the hematological malignancy is relapsed or refractory follicular lymphoma (FL).

[0174] In some embodiments, the hematological malignancy is a hematological malignancy classified as high-risk, ie, high-risk CLL or high-risk SLL.

[0175] B-cell lymphoproliferative disorders (BCLDs) are hematological tumors, including non-Hodgkin's lymphoma, multiple myeloma, and leukemia, among others. BCLDs can arise in either lymphoid tissue (as in lymphomas) or bone marrow (as in leukemia and myeloma), all of which are associated with uncontrolled growth of lymphocytes or white blood cells. There are many subtypes of BCLD, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). The disease course and treatment of BCLD depend on the BCLD subtype; however, even within each subtype, clinical symptoms, morphological appearance, and response to treatment are heterogeneous.

[0176] Malignant lymphoma is a malignant transformation of cells that reside predominantly in lymphoid tissues. Two groups of malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphoma invade tissues of the reticuloendothelial system. However, they differ in the neoplastic cell of origin, the site of disease, the presence of systemic symptoms, and response to treatment (Freedman et al., "Non-Hodgkin's Lymphomas," Chapter 134, Cancer Medicine, (approved publication of the American Cancer Society, BC Decker Inc., Hamilton, Ontario, 2003)).

[0177] Non-Hodgkin lymphoma

[0178] Disclosed herein, in certain embodiments, is a method of treating non-Hodgkin's lymphoma in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1.

[0179] Further disclosed herein, in certain embodiments, are methods of treating relapsed or refractory non-Hodgkin's lymphoma in an individual in need thereof, the methods comprising administering to the individual a therapeutically effective amount of Compound 1. In some embodiments, the non-Hodgkin's lymphoma is relapsed or refractory large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, or relapsed or refractory CLL.

[0180] Non-Hodgkin's lymphoma (NHL) is a diverse group of malignant tumors predominantly of B-cell origin. NHL can develop in any organ associated with the lymphatic system, such as the spleen, lymph nodes, or tonsils, and can occur at any age. NHL is typically characterized by lymphadenopathy, fever, and weight loss. NHL is classified as either B-cell or T-cell NHL. Lymphomas associated with lymphoproliferative disorders after bone marrow or stem cell transplantation are usually B-cell NHL. In the Working Formulation classification system, NHLs are divided into low-grade, intermediate-grade, or high-grade categories based on their natural history (see "The Non-Hodgkin's Lymphoma Pathologic Classification Project," Cancer 49(1982):2112-2135). Low-grade lymphomas are indolent and have a median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311:1471-1475). Chemotherapy can induce remission in the majority of indolent lymphomas, but cures are rare, and most patients eventually relapse and require further treatment. Intermediate- and high-grade lymphomas are more aggressive tumors, but they have a greater chance of being cured with chemotherapy. However, a significant proportion of these patients relapse and require further treatment.

[0181] A non-exclusive list of B-cell NHLs includes Burkitt lymphoma (e.g., endemic Burkitt lymphoma and sporadic Burkitt lymphoma), cutaneous B-cell lymphoma, cutaneous marginal zone lymphoma (MZL), diffuse large cell lymphoma (DLBCL), diffuse mixed small and large cell lymphoma (Diffuse Mixed Small and Large Cell Lymphoma), and diffuse large cell lymphoma (Diffuse Mixed Small and Large Cell Lymphoma). Lympoma), diffuse small round cell, small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, follicular lymphoma, follicular small round cell (grade 1), follicular mixed small and large round cell (grade 2), follicular large cell (grade 3), intravascular large B-cell lymphoma, intravascular lymphomatosis, large immunoblastic lymphoma, large cell lymphoma (LCL), lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma (MCL), immunoblastic large cell lymphoma, These include precursor B-lymphoblastic lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), extranodal marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, mediastinal large B-cell lymphoma, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, early mediastinal B-cell lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, Waldenstrom's macroglobulinemia, and early central nervous system (CNS) lymphoma. Additional non-Hodgkin's lymphomas are contemplated within the scope of the present invention and will be apparent to those skilled in the art.

[0182] DLBCL

[0183] Disclosed herein, in certain embodiments, is a method of treating DLBCL in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory DLBCL in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0184] As used herein, the term "diffuse large B-cell lymphoma (DLBCL)" refers to a neoplasm of germinal center B lymphocytes with a dispersed growth pattern and a high-to-moderate proliferation index. DLBCL represents approximately 30% of all lymphomas and can exist with a variety of morphologic variations, including germinal center cell, immunoblastic, T cell / histiocyte-rich, anaplastic, and plasmablastic subtypes. Genetic testing has shown that different subtypes of DLBCL exist. These subtypes appear to have different appearances (prognoses) and responses to treatment. DLBCL can affect any age group, but most often occurs in older adults (the average age is in the mid-60s).

[0185] Disclosed herein, in certain embodiments, is a method for treating diffuse large B-cell lymphoma, activated B-cell-like subtype (ABC-DLBCL) in an individual in need thereof, comprising administering to the individual an irreversible Btk inhibitor in an amount ranging from 300 mg / day to 1000 mg / day. The ABC subtype of diffuse large B-cell lymphoma (ABC-DLBCL) is thought to arise from post-germinal center B cells that are arrested during plasma differentiation. The ABC subtype of DLBCL (ABC-DLBCL) accounts for approximately 30% of all DLBCL diagnoses. It is considered the most difficult to treat of the DLBCL molecular subtypes, and patients diagnosed with ABC-DLBCL typically exhibit significantly reduced survival rates compared to individuals with other types of DLBCL. ABC-DLBCL is most commonly associated with chromosomal translocations that deregulate the germinal center master regulator BCL6 and mutations that inactivate the PRDM1 gene, which encodes a transcriptional repressor required for plasma cell differentiation.

[0186] A signaling pathway particularly relevant in the pathogenesis of ABC-DLBCL is that mediated by the nuclear factor (NF)-κB transcription complex. The NF-κB family contains five members (p50, p52, p65, c-rel, and RelB), which form homodimers or heterodimers and function as transcription factors mediating various proliferation, apoptosis, inflammatory, and immune responses, and are critical for normal B cell progression and survival. NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and survival. Consequently, many different types of human tumors have misregulated NF-κB; i.e., NF-κB is constitutively active. Active NF-κB turns on the expression of genes that keep cells proliferating and protect them from diseases that cause them to die via apoptosis.

[0187] The dependence of ABC DLBCLs on NF-κB depends on a signaling pathway upstream of IkB kinase, which is composed of CARD11, BCL10, and MALT1 (the CBM complex). Interference with the CBM pathway abolishes NF-κB signaling in ABC DLBCL cells and induces apoptosis. While the molecular basis for constitutive activity of the NF-κB pathway is currently under investigation, several somatic mutations in the genome of ABC DLBCLs explicitly invoke this pathway. For example, somatic mutations in the coiled-coil domain of CARD11 in DLBCLs enable this signaling scaffold protein to spontaneously nucleate from protein-protein interactions with MALT1 and BCL10, leading to IKK activity and NF-κB activation. Constitutive activity of the B cell receptor signaling pathway is linked to NF-κB activation in ABC DLBCLs by wild-type CARD11, which is associated with mutations in the cytoplasmic tails of the B cell receptor subunits CD79A and CD79B. Oncogenic activating mutations in the signaling adaptor MYD88 activate NF-κB and synergize with B cell receptor signaling in sustaining ABC DLBCL cell survival. In addition, inactivating mutations in the NF-κB pathway negative regulator (A20) occur almost exclusively in ABC DLBCL.

[0188] Indeed, genetic alterations affecting multiple components of the NF-κB signaling pathway have been identified in more than 50% of ABC-DLBCL patients in recent years. These lesions promote constitutive NF-κB activation, thereby contributing to lymphoma growth. These include mutations in CARD11 (~10% of cases), a lymphocyte-specific cytoplasmic scaffold protein that, together with MALT1 and BCL10, forms the BCR signalosome, which relays signals from antigen receptors to downstream mediators of NF-κB activation. Even a larger fraction of cases (~30%) carry biallelic genetic lesions that inactivate the negative NF-κB regulator A20. Furthermore, elevated expression of NF-κB target genes has been observed in ABC-DLBCL tumor samples. For example, U. Klein et al., (2008), Nature Reviews Immunology 8:22-23; RE Davis et al., (2001), Journal of Experimental Medicine 194:1861-1874; G. Lentz et al., (2008), Science 319:1676-1679; M. Compagno et al., (2009), Nature 459:712-721; and L. Srinivasan et al., (2009), Cell 139:573-586).

[0189] DLBCL cells of the ABC subtype, such as OCI-Ly10, have chronically active BCR signaling and are highly sensitive to the Btk inhibitors described herein. The irreversible Btk inhibitors described herein potently and irreversibly inhibit the proliferation of OCI-Ly10 (EC 50 Continuous exposure = 10 nM, EC 50(1-hour pulse = 50 nM). In addition, induction of apoptosis, as indicated by caspase activation, Annexin-V flow cytometry, and an increase in the sub-GO fraction, is observed in OCILy10. Sensitive and refractory cells express Btk at similar levels, and the Btk active site is fully occupied by the inhibitor in both, as shown using a fluorescently labeled affinity probe. OCI-Ly10 cells are shown to have chronically active BCR signaling to NF-κB, a dose-dependent inhibition by the Btk inhibitors described herein. The activity of Btk inhibitors in the cell lines discussed herein was also characterized by comparing signaling profiles (Btk, PLCγ, ERK, NF-κB, AKT), cytokine secretion, and mRNA expression profiles with and without BCR stimulation, and significant differences in these profiles were observed, leading to clinical biomarkers that could identify patient populations most sensitive to Btk inhibitor treatment. See U.S. Patent No. 7,711,492 and Staudt et al., Nature, Vol. 463, Jan. 7, 2010, pp. 88-92, the contents of which are incorporated by reference in their entirety.

[0190] follicular lymphoma

[0191] Disclosed herein, in certain embodiments, is a method of treating follicular lymphoma in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory follicular lymphoma in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0192] As used herein, the term "follicular lymphoma" refers to any of the various types of non-Hodgkin's lymphoma in which lymphoma cells are clustered in nodules or follicles. The cells tend to grow in a circular or nodular pattern in the lymph nodes, hence the term "follicular." The average age of people with this lymphoma is about 60 years old.

[0193] CLL / SLL

[0194] Disclosed herein, in certain embodiments, is a method of treating CLL or SLL in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory CLL or SLL in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0195] Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL / SLL) are generally thought of as the same disease with slightly different onsets. Where the cancer cells collect determines whether it is called CLL or SLL. When cancer cells are found primarily in lymph nodes (lima-bean-shaped structures in the lymphatic system (a system of small blood vessels found primarily in the body)), it is called SLL. SLL accounts for approximately 5% to 10% of all lymphomas. When most of the cancer cells are in the bloodstream and bone marrow, it is called CLL.

[0196] Both CLL and SLL are slow-growing diseases, but CLL, which is by far the most common, tends to grow slowly. CLL and SLL are treated in the same way. They are not usually considered curable with standard treatments, but most patients live longer than 10 years, depending on the stage and growth rate of the disease. Sometimes over time, these slow-growing lymphomas can transform into more aggressive forms of lymphoma.

[0197] Chronic lymphocytic leukemia (CLL) is the most common type of leukemia. It is estimated that 100,760 people in the United States are living with or in remission from CLL. Most people (>75%) newly diagnosed with CLL are over the age of 50. Currently, CLL treatment focuses on controlling the disease and its symptoms rather than definitive cure. CLL is treated with chemotherapy, radiation therapy, biological therapy, or bone marrow transplant. Symptoms are sometimes treated surgically (splenectomy for splenomegaly) or with radiation therapy (to "debulk" lymphadenopathy). CLL progresses slowly in most cases and is generally considered untreatable. Certain CLLs are classified as high-risk. As used herein, "high-risk CLL" refers to CLL characterized by at least one of the following: 1) 17p13-; 2) 11q22-; 3) unmutated IgVH with ZAP-70+ and / or CD38+; or 4) trisomy 12.

[0198] CLL treatment is typically administered when a patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.

[0199] Small lymphocytic leukemia (SLL) is very similar to CLL and is also a cancer of B cells. In SLL, abnormal lymphocytes primarily affect lymph nodes. However, in CLL, abnormal cells primarily affect the blood and bone marrow. The spleen can be affected in both conditions. SLL accounts for approximately 1 in 25 cases of non-Hodgkin's lymphoma. It can occur at any time from adolescence to old age, but is rare in patients under 50 years of age. SLL is considered an indolent lymphoma. This means that the disease progresses very slowly, and patients tend to live many years after diagnosis. However, most patients are diagnosed with advanced disease, and although SLL responds well to various chemotherapy agents, it is generally considered incurable. While some cancers tend to occur more frequently in one gender than the other, cases and deaths from SLL are equally distributed between men and women. The average age at diagnosis is 60 years.

[0200] SLL is indolent but persistently progressive. The usual pattern of the disease is periods of disease remission with high response rates to radiation and / or chemotherapy. This is followed by months or years of inevitable relapse. Retreatment again leads to response, but the disease returns to its original state. This means that while the short-term prognosis for SLL is quite good, over time, many patients develop the fatal complications of recurrent disease. Given the age of individuals typically diagnosed with CLL and SLL, there is a need in the art for a simple, effective treatment of the disease with minimal side effects that does not interfere with the patient's quality of life. The present invention fulfills this long-standing need in the art.

[0201] Mantle cell lymphoma

[0202] Disclosed herein, in certain embodiments, is a method of treating mantle cell lymphoma in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory mantle cell lymphoma in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0203] As used herein, the term "mantle cell lymphoma" refers to a subtype of B-cell lymphoma characterized by CD5-positive, antigen-naive pregerminal center B cells within the mantle zone surrounding typical germinal center follicles. MCL cells typically overexpress cyclin D1 due to a t(11:14) chromosomal translocation in DNA. More specifically, the translocation is at t(11;14)(q13;q32). Only approximately 5% of lymphomas are of this type. The cells are small to medium in size. Humans are most frequently affected. The average age of patients is in the early 60s. Lymphatic involvement is usually extensive at diagnosis, involving the lymph nodes, bone marrow, and, very frequently, the spleen. Mantle cell lymphoma is not a very fast-growing lymphoma, but it is difficult to treat.

[0204] Marginal zone B-cell lymphoma

[0205] Disclosed herein, in certain embodiments, is a method of treating marginal zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory marginal zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0206] As used herein, the term "marginal zone B-cell lymphoma" refers to a group of related B-cell neoplasms that involve lymphoid tissue in the marginal zone (the patchy area outside the mantle of the follicle). Marginal zone lymphomas account for approximately 5% to 10% of lymphomas. The cells in these lymphomas appear small under a microscope. There are three major types of marginal zone lymphoma: extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, and splenic marginal zone lymphoma.

[0207] MALT

[0208] Disclosed herein, in certain embodiments, is a method of treating MALT in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory MALT in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0209] As used herein, the term "mucosa-associated lymphoid tissue (MALT) lymphoma" refers to the extranodal manifestation of marginal zone lymphoma. Most MALT lymphomas are low-grade, but a small number either initially manifest as intermediate-grade non-Hodgkin's lymphoma (NHL) or evolve from a low-grade form. Most MALT lymphomas arise in the stomach, and approximately 70% of gastric MALT lymphomas are associated with Helicobacter pylori infection. Various cytogenetic abnormalities have been identified, the most common being trisomy or t(11;18). Many of these other MALT lymphomas have also been associated with bacterial or viral infections. The average age of patients with MALT lymphoma is approximately 60 years.

[0210] Marginal zone lymph node B-cell lymphoma

[0211] Disclosed herein, in certain embodiments, is a method of treating marginal node zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory marginal node zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0212] The term "marginal zone B-cell lymphoma" refers to an indolent B-cell lymphoma that is mostly found in lymph nodes. The disease is rare, accounting for only 1% of all non-Hodgkin's lymphomas (NHL). It is most commonly diagnosed in older patients, and women are more likely to be affected than men. The disease is classified as marginal zone lymphoma because mutations occur in the marginal zone of B cells. Because of its restriction in the lymph nodes, the disease is also classified as nodal.

[0213] Splenic marginal zone B-cell lymphoma

[0214] Disclosed herein, in certain embodiments, is a method of treating splenic marginal zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory splenic marginal zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0215] The term "splenic marginal zone B-cell lymphoma" refers to a specific low-grade small B-cell lymphoma found in the World Health Organization classification. Characteristic features include a moderate lymphocytosis of splenomegaly with villous morphology, an intrasinusoidal pattern of involvement of various organs, especially the bone marrow, and a relatively indolent period. Tumor progression with increasingly blast morphology and aggressive behavior is observed in a minority of patients. Molecular and cytogenetic studies have shown mixed results, likely due to the lack of standardized diagnostic criteria.

[0216] Burkitt lymphoma

[0217] Disclosed herein, in certain embodiments, is a method of treating Burkitt lymphoma in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory Burkitt lymphoma in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0218] The term "Burkitt lymphoma" refers to a type of non-Hodgkin's lymphoma (NHL) that commonly affects children. It is a highly aggressive type of B-cell lymphoma that frequently arises from and involves body parts other than lymph nodes. Despite its fast-growing nature, Burkitt lymphoma is usually treatable with modern intensive care. There are two widespread types of Burkitt lymphoma: the disseminated and endemic variants.

[0219] Endemic Burkitt lymphoma: The disease affects children far more than adults and is associated with Epstein-Barr virus (EBV) infection in 95% of cases. It originates in equatorial Africa, where approximately half of all childhood cancers are Burkitt lymphoma. It characteristically has a high probability of involvement of the jawbone, a highly distinctive feature that is rare in sporadic Burkitt lymphoma. It also commonly involves the abdomen.

[0220] Sporadic Burkitt lymphoma: The type of Burkitt lymphoma that affects the rest of the world, including Europe and the Americas, is the sporadic type. Again, it is primarily a disease of children. Direct evidence of Epstein-Barr virus (EBV) infection is present in one in five patients, but the link between EBV and the disease is not as strong as in the endemic variant. More than lymph node involvement, the abdomen is prominently affected in more than 90% of children. Bone marrow involvement is more common than in the sporadic variant.

[0221] Waldenström macroglobulinemia

[0222] Disclosed herein, in certain embodiments, is a method of treating Waldenstrom's macroglobulinemia in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory Waldenstrom's macroglobulinemia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0223] Waldenström's macroglobulinemia, also known as lymphoplasmacytic lymphoma, is a cancer involving a subtype of white blood cells called lymphocytes. It is characterized by uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized by lymphoma cells that produce an antibody called immunoglobulin M (IgM). IgM antibodies circulate in the blood in large quantities, causing the liquid portion of the blood to thicken like syrup. This can lead to reduced blood flow to many organs, which can cause problems with vision (due to poor circulation in the blood vessels behind the eyes), and neurological problems (such as headaches, dizziness, and confusion) caused by poor blood flow in the brain. Other symptoms can include feelings of fatigue and weakness and a tendency to bleed easily. While the underlying etiology is not fully understood, many risk factors have been identified, including the location 6p21.3 on chromosome 6. There is a two- to three-fold increased risk of developing WM in people with a personal history of autoantibodies and particularly high-risk autoimmune diseases associated with hepatitis, human immunodeficiency virus, and rickettsiosis.

[0224] Multiple myeloma

[0225] Disclosed herein, in certain embodiments, is a method of treating myeloma in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory myeloma in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0226] Multiple myeloma, also known as MM, myeloma, plasma cell myeloma, or Kahler's disease (after Otto Kahler), is a cancer of the white blood cells known as plasma cells. Plasma cells, a type of B cell, are an important part of the immune system in humans and other vertebrates, responsible for antibody production. They are produced in the bone marrow and transported through the lymphatic system.

[0227] leukemia

[0228] Disclosed herein, in certain embodiments, is a method of treating leukemia in an individual in need thereof, the method comprising administering to the individual an amount of Compound 1. Also disclosed herein, in certain embodiments, is a method of treating relapsed or refractory leukemia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound 1.

[0229] Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase in blood cells, usually leukocytes (white blood cells). Leukemia is a broad term that covers a range of diseases. The primary division is between its acute and chronic forms: (i) acute leukemia is characterized by a rapid increase in immature blood cells. This crowding prevents the bone marrow from producing healthy blood cells. Emergency treatment is required for acute leukemia due to the rapid progression and accumulation of malignant cells, which then spread to the bloodstream and other organs of the body. The acute form of leukemia is the most common form of leukemia in children; (ii) chronic leukemia is distinguished by the excessive accumulation of relatively mature, yet still abnormal, white blood cells. Because it typically takes months or years to progress, cells are produced at a much higher rate than normal cells, resulting in a large number of abnormal white blood cells in the blood. Chronic leukemia most often occurs in older people, but theoretically can occur in any age group. In addition, the disease is subdivided according to which blood cell types are affected, into lymphoblastic or lymphocytic leukemia, and myeloid or osteosarcomatous leukemia: (i) lymphoblastic or lymphocytic leukemia, in which cancerous changes occur in a type of bone marrow cell that normally progresses to form lymphocytes, immune system cells that fight infection; (ii) myeloid or osteosarcomatous leukemia, in which cancerous changes occur in a type of bone marrow cell that normally progresses to form red blood cells, some other type of white blood cells, and platelets.

[0230] Within these major categories, there are various subcategories, including, but not limited to, acute lymphoblastic leukemia (ALL), B-cell precursor acute lymphoblastic leukemia (precursor B-ALL; also called precursor B-lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and hairy cell leukemia (HCL). Accordingly, in certain embodiments, disclosed herein are methods of treating acute lymphoblastic leukemia (ALL), B-cell precursor acute lymphoblastic leukemia (precursor B-ALL; also called precursor B-lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hairy cell leukemia (HCL) in an individual in need thereof, the methods comprising administering to the individual an amount of Compound 1. In some embodiments, the leukemia is relapsed or refractory leukemia. In some embodiments, the leukemia is relapsed or refractory acute lymphoblastic leukemia (ALL), relapsed or refractory B-cell precursor acute lymphoblastic leukemia (precursor B-ALL; also called precursor B-lymphoblastic leukemia), relapsed or refractory acute myeloid leukemia (AML), relapsed or refractory chronic myeloid leukemia (CML), or relapsed or refractory hairy cell leukemia (HCL).

[0231] Symptoms, diagnostic tests, and prognostic tests for each of the aforementioned diseases are known. See, e.g., Harrison's Principles of Internal Medicine, 16th ed., 2004, The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal 3(24), and the "Revised European American Lymphoma" (REAL) classification system (see, e.g., the website maintained by the National Cancer Institute).

[0232] A number of animal models are useful for establishing a range of effective doses of an irreversible Btk inhibitor compound, such as Compound 1, for the treatment of any of the aforementioned diseases.

[0233] The therapeutic effect of Compound 1 for any one of the aforementioned diseases can be optimized over the course of treatment. For example, a subject being treated can undergo a diagnostic evaluation to correlate the alleviation of disease symptoms or conditions to the inhibition of in vivo Btk activity achieved by administration of a dose of Compound 1. Cellular assays known in the art can be used to determine the in vivo activity of Btk in the presence or absence of an irreversible Btk inhibitor. For example, because activated Btk is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specific immunocytochemical staining of P-Y223 or P-Y551-positive cells can be used to detect or quantitate Bkt activation in a cell population (e.g., by FACS analysis of stained vs. unstained cells). See, e.g., Nishitani et al. (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus, the amount of a Btk inhibitor compound administered to a subject can be increased or decreased as needed to maintain a level of Btk inhibition that is optimal for treating the subject's disease condition.

[0234] Compound 1 irreversibly inhibits Btk and can be used to treat mammals suffering from Bruton's tyrosine kinase-dependent or Bruton's tyrosine kinase-mediated diseases or disorders, including, but not limited to, cancer, autoimmune and other inflammatory diseases. Compound 1 has demonstrated efficacy in a wide variety of diseases and disorders, as described herein.

[0235] In some embodiments, Compound 1 is used in the manufacture of a medicament for treating any of the aforementioned diseases (e.g., an autoimmune disease, an inflammatory disease, an allergic disorder, a B-cell proliferative disorder, or a thromboembolic disorder).

[0236] <Compound 1 and pharmaceutically acceptable salts thereof> The Btk inhibitory compound described herein (i.e., Compound 1) is selective for Btk and kinases that have a cysteine ​​residue at the amino acid sequence position of the tyrosine kinase that is homologous to the amino acid sequence position of cysteine ​​481 in Btk. The Btk inhibitory compound can form a covalent bond with cysteine ​​481 of Btk (e.g., via a Michael reaction).

[0237] "Compound 1" or "1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one" or "1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one" or "2-propen-1-one, 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl-" or ibrutinib, or other suitable name, refers to a compound having the following structure:

[0238] [ka]

[0239] A wide variety of pharmaceutically acceptable salts may be formed from Compound 1, including:

[0240] Acid addition salts formed by reacting Compound 1 with organic acids (including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxylalkanoic acids, alkanediol (alkanediol) acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc.), including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0241] Acid addition salts formed by reacting compound 1 with inorganic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.

[0242] The term "pharmaceutically acceptable salt," in reference to Compound 1, refers to a salt of Compound 1 that does not cause significant irritation to the mammal to which it is administered and that does not substantially abrogate the biological activity and properties of the compound.

[0243] It should be understood that a reference to a pharmaceutically acceptable salt includes its solvent addition forms (solvates). Solvates contain either stoichiometric or non-stoichiometric amounts of the solvate and are formed during the process of product formation or isolation with pharmaceutically acceptable solvents (such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc.). In one embodiment, solvates are formed using, but not limited to, Class 3 solvents. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of Compound 1, or a pharmaceutically acceptable salt thereof, are conveniently prepared or formed during the processes described herein. In some embodiments, solvates of Compound 1 are anhydrous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, exists in an unsolvated form. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, exists in an unsolvated form and is anhydrous.

[0244] In yet other embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is prepared in various forms, including, but not limited to, amorphous phases, crystalline forms, milled forms, and nanoparticulate forms. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is amorphous. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is amorphous and anhydrous. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is crystalline. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is crystalline and anhydrous.

[0245] In some embodiments, Compound 1 is prepared as outlined in US Pat. No. 7,514,444.

[0246] <Amorphous compound 1> In some embodiments, Compound 1 is amorphous and anhydrous. In some embodiments, Compound 1 is amorphous. In some embodiments, amorphous Compound 1 has an X-ray powder diffraction (XRPD) pattern that indicates a lack of crystallinity.

[0247] <Compound 1, Form A> In some embodiments, Compound 1 is crystalline. In some embodiments, Compound 1 is in crystalline form A. Crystalline form A of Compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 1 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.7 ± 0.1° 2-theta, 13.6 ± 0.1° 2-theta, 16.1 ± 0.1° 2-theta, 18.9 ± 0.1° 2-theta, 21.3 ± 0.1° 2-theta, and 21.6 ± 0.1° 2-theta; (c) Nearly identical X-ray powder diffraction (XRPD) patterns after storage at 40°C and 75% RH for at least 1 week; (d) Nearly identical X-ray powder diffraction (XRPD) patterns after storage at 25°C and 97% RH for at least one week; (e) Infrared (IR) spectrum, roughly similar to that shown in Figure 2 ; (f) Approximately 1584cm -1 , approx. 1240cm -1 , approx. 1147cm -1 , approx. 1134cm -1 , approximately 1099 cm -1 , and approximately 1067 cm -1 A weak peak in the infrared (IR) spectrum at ; (g) DSC thermogram roughly similar to that shown in Figure 3 ; (h) Thermogravimetric analysis (TGA) thermogram roughly similar to that shown in Figure 4 ; (i) a DSC thermogram with an endotherm with an onset at about 154°C and a peak at about 157°C, and an exotherm at about 159°C; (j) non-hygroscopic; (k) an observed aqueous solubility of about 0.013 mg / mL at about pH 8; Or, (n) A combination thereof.

[0248] In some embodiments, Compound 1 Form A is characterized by having at least two properties selected from (a) through (k). In some embodiments, Compound 1 Form A is characterized by having at least three properties selected from (a) through (k). In some embodiments, Compound 1 Form A is characterized by having at least four properties selected from (a) through (k). In some embodiments, Compound 1 Form A is characterized by having at least five properties selected from (a) through (k). In some embodiments, Compound 1 Form A is characterized by having at least six properties selected from (a) through (k). In some embodiments, Compound 1 Form A is characterized by having at least seven properties selected from (a) through (k). In some embodiments, Compound 1 Form A is characterized by having at least eight properties selected from (a) through (k). In some embodiments, Compound 1 Form A is characterized by having at least nine properties selected from (a) through (k). In some embodiments, Compound 1 Form A is characterized by having at least ten properties selected from (a) through (k). In some embodiments, Form A of Compound 1 is characterized by having properties (a) through (k).

[0249] In some embodiments, Form A has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 1. In some embodiments, Form A has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.7±0.1°2-theta, 13.6±0.1°2-theta, 16.1±0.1°2-theta, 18.9±0.1°2-theta, 21.3±0.1°2-theta, and 21.6±0.1°2-theta. In some embodiments, Form A has substantially the same X-ray powder diffraction (XRPD) pattern after storage at 40°C and 75% RH for at least 1 week. In some embodiments, Form A has substantially the same X-ray powder diffraction (XRPD) pattern after storage at 25°C and 97% RH for at least 1 week.

[0250] In some embodiments, Form A has an infrared (IR) spectrum substantially similar to that shown in Figure 2. In some embodiments, Form A has an IR spectrum at about 1584 cm -1 , approx. 1240cm -1 , approx. 1147cm -1 , approx. 1134cm -1 , approximately 1099 cm -1 , and approximately 1067 cm -1 It has a weak peak in the infrared (IR) spectrum at

[0251] In some embodiments, Form A has a DSC thermogram substantially similar to that shown in Figure 3. In some embodiments, Form A has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 4. In some embodiments, Form A has a DSC thermogram with an endotherm with an onset at about 154°C and a peak at about 157°C, and an exotherm at about 159°C.

[0252] In some embodiments, Form A is non-hygroscopic.

[0253] In some embodiments, Form A has an observed aqueous solubility of about 0.013 mg / mL at about pH 8.

[0254] In some embodiments, Form A was obtained from ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole, acetone, heptane, a mixture of methanol / water, or a mixture of acetone / heptane. In some embodiments, Form A was obtained from ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole, acetone, heptane, or a mixture of acetone / heptane.

[0255] In some embodiments, Form A is unsolvated. In some embodiments, Form A is anhydrous.

[0256] <Compound 1, Form B> In some embodiments, Compound 1 is crystalline. In some embodiments, Compound 1 is in crystalline form B. Crystalline form B of Compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 5 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.2 ± 0.1° 2-theta, 10.2 ± 0.1° 2-theta, 16.5 ± 0.1° 2-theta, 18.5 ± 0.1° 2-theta, and 20.8 ± 0.1° 2-theta; (c) Nearly identical X-ray powder diffraction (XRPD) patterns after storage at 40°C and 75% RH for at least 1 week; (d) Nearly identical X-ray powder diffraction (XRPD) patterns after storage at 25°C and 97% RH for at least one week; (e) Infrared (IR) spectrum, roughly similar to that shown in Figure 6 ; (f) Approximately 1586cm -1 , approx. 1573cm -1 , approx. 1562cm -1 , approx. 1229cm -1 , approx. 1141cm -1 , approx. 1103cm -1 , approximately 1056 cm -1 , and approximately 1033 cm -1 A weak peak in the infrared (IR) spectrum at ; (g) DSC thermogram roughly similar to that shown in Figure 7 ; (h) Thermogravimetric analysis (TGA) thermogram roughly similar to that shown in Figure 8 ; (i) a DSC thermogram with an endotherm with an onset at about 99-106°C and a peak at about 115-118°C; (j) an observed aqueous solubility of about 0.0096 mg / mL at about pH 7.42; Or, (k) Combinations thereof.

[0257] In some embodiments, Form B of Compound 1 is characterized by having at least two of the properties selected from (a) through (j). In some embodiments, Form B of Compound 1 is characterized by having at least three of the properties selected from (a) through (j). In some embodiments, Form B of Compound 1 is characterized by having at least four of the properties selected from (a) through (j). In some embodiments, Form B of Compound 1 is characterized by having at least five of the properties selected from (a) through (j). In some embodiments, Form B of Compound 1 is characterized by having at least six of the properties selected from (a) through (j). In some embodiments, Form B of Compound 1 is characterized by having at least seven of the properties selected from (a) through (j). In some embodiments, Form B of Compound 1 is characterized by having at least eight of the properties selected from (a) through (j). In some embodiments, Form B of Compound 1 is characterized by having at least nine of the properties selected from (a) through (j). In some embodiments, Form B of Compound 1 is characterized by having properties (a) through (j).

[0258] In some embodiments, Form B has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 5. In some embodiments, Form B has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.2±0.1°2-theta, 10.2±0.1°2-theta, 16.5±0.1°2-theta, 18.5±0.1°2-theta, and 20.8±0.1°2-theta. In some embodiments, Form B has substantially the same X-ray powder diffraction (XRPD) pattern after storage at 40°C and 75% RH for at least 1 week. In some embodiments, Form B has substantially the same X-ray powder diffraction (XRPD) pattern after storage at 25°C and 97% RH for at least 1 week.

[0259] In some embodiments, Form B has an infrared (IR) spectrum substantially similar to that shown in Figure 6. In some embodiments, Form B has an IR spectrum at about 1586 cm -1 , approx. 1573cm -1 , approx. 1562cm -1 , approx. 1229cm -1 , approx. 1141cm -1 , approx. 1103cm -1 , approximately 1056 cm -1 , and approximately 1033 cm -1 It has a weak peak in the infrared (IR) spectrum at

[0260] In some embodiments, Form B has a DSC thermogram substantially similar to that shown in Figure 7. In some embodiments, Form B has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 8. In some embodiments, Form B has a DSC thermogram with an onset at about 99-106°C and an endotherm with a peak at about 115-118°C.

[0261] In some embodiments, Form B has an observed aqueous solubility of about 0.0096 mg / mL at a pH of about 7.42.

[0262] In some embodiments, Form B was obtained from a mixture of methanol and water.

[0263] In some embodiments, Form B is unsolvated. In some embodiments, Form B is anhydrous.

[0264] <Compound 1, Form C> In some embodiments, Compound 1 is crystalline. In some embodiments, Compound 1 is in crystalline form C. Crystalline form C of Compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 9 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0 ± 0.1° 2-theta, 14.0 ± 0.1° 2-theta, 15.7 ± 0.1° 2-theta, 18.2 ± 0.1° 2-theta, 19.1 ± 0.1° 2-theta, 19.5 ± 0.1° 2-theta, 20.3 ± 0.1° 2-theta, 22.1 ± 0.1° 2-theta, and 22.9 ± 0.1° 2-theta; (c) DSC thermogram roughly similar to that shown in Figure 10 ; (d) Thermogravimetric analysis (TGA) thermogram roughly similar to that shown in Figure 11 ; (e) DSC thermogram with an endotherm with an onset at about 99-106°C and a peak at about 115-118°C; Or, (f) combinations thereof.

[0265] In some embodiments, Form C of Compound 1 is characterized by having at least two of the properties selected from (a) through (e). In some embodiments, Form C of Compound 1 is characterized by having at least three of the properties selected from (a) through (e). In some embodiments, Form C of Compound 1 is characterized by having at least four of the properties selected from (a) through (e). In some embodiments, Form C of Compound 1 is characterized by having properties (a) through (e).

[0266] In some embodiments, Form C has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 9. In some embodiments, Form C has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0±0.1°2-theta, 14.0±0.1°2-theta, 15.7±0.1°2-theta, 18.2±0.1°2-theta, 19.1±0.1°2-theta, 19.5±0.1°2-theta, 20.3±0.1°2-theta, 22.1±0.1°2-theta, and 22.9±0.1°2-theta.

[0267] In some embodiments, Form C has a DSC thermogram substantially similar to that shown in Figure 10. In some embodiments, Form C has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 11. In some embodiments, Form C has a DSC thermogram with an endotherm with an onset at about 134-135°C and a peak at about 137-139°C.

[0268] In some embodiments, Form C was obtained from a mixture of methanol and water. In some embodiments, Form C was obtained from methanol.

[0269] In some embodiments, Form C is unsolvated. In some embodiments, Form C is anhydrous.

[0270] <Compound 1, Form D> In some embodiments, Compound 1 is crystalline. In some embodiments, Compound 1 is crystalline form D. Crystalline form D of Compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 12 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.2 ± 0.1° 2-theta, 8.0 ± 0.1° 2-theta, 9.2 ± 0.1° 2-theta, 14.5 ± 0.1° 2-theta, 18.5 ± 0.1° 2-theta, 19.5 ± 0.1° 2-theta, 20.7 ± 0.1° 2-theta, 21.0 ± 0.1° 2-theta, 21.9 ± 0.1° 2-theta, and 22.4 ± 0.1° 2-theta; (c) Thermogravimetric analysis (TGA) thermogram roughly similar to that shown in Figure 13 ; Or, (d) combinations thereof.

[0271] In some embodiments, Form D of Compound 1 is characterized by having at least two of the properties selected from (a) through (c). In some embodiments, Form D of Compound 1 is characterized by having properties (a), (b), and (c).

[0272] In some embodiments, Form D has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 12. In some embodiments, Form D has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.2±0.1°2-theta, 8.0±0.1°2-theta, 9.2±0.1°2-theta, 14.5±0.1°2-theta, 18.5±0.1°2-theta, 19.5±0.1°2-theta, 20.7±0.1°2-theta, 21.0±0.1°2-theta, 21.9±0.1°2-theta, and 22.4±0.1°2-theta.

[0273] In some embodiments, Form D has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in FIG.

[0274] In some embodiments, Form D was obtained from methyl isobutyl ketone (MIBK). In some embodiments, Form D is solvated. In some embodiments, crystalline Form D is solvated with methyl isobutyl ketone (MIBK).

[0275] <Compound 1, Form E> In some embodiments, Compound 1 is crystalline. In some embodiments, Compound 1 is crystalline form E. Crystalline form E of Compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 14 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.8 ± 0.1° 2-theta, 8.8 ± 0.1° 2-theta, 16.1 ± 0.1° 2-theta, 18.1 ± 0.1° 2-theta, 19.3 ± 0.1° 2-theta, 19.5 ± 0.1° 2-theta, 20.5 ± 0.1° 2-theta, 21.6 ± 0.1° 2-theta, and 25.2 ± 0.1° 2-theta; (c) DSC thermogram roughly similar to that shown in Figure 15 ; (d) Thermogravimetric analysis (TGA) thermogram roughly similar to that shown in Figure 15 ; Or, (e) combinations thereof.

[0276] In some embodiments, Form E of Compound 1 is characterized by having at least two of the properties selected from (a) through (d). In some embodiments, Form E of Compound 1 is characterized by having at least three of the properties selected from (a) through (d). In some embodiments, Form E of Compound 1 is characterized by having properties (a) through (d).

[0277] In some embodiments, Form E has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 14. In some embodiments, Form E has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.8±0.1°2-theta, 8.8±0.1°2-theta, 16.1±0.1°2-theta, 18.1±0.1°2-theta, 19.3±0.1°2-theta, 19.5±0.1°2-theta, 20.5±0.1°2-theta, 21.6±0.1°2-theta, and 25.2±0.1°2-theta.

[0278] In some embodiments, Form E has a DSC thermogram substantially similar to that shown in Figure 15. In some embodiments, Form E has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 15.

[0279] In some embodiments, Form E was obtained from toluene.

[0280] In some embodiments, Form E is solvated. In some embodiments, Form E is solvated with toluene.

[0281] <Compound 1, Form F> In some embodiments, Compound 1 is crystalline. In some embodiments, Compound 1 is crystalline form F. Crystalline form F of Compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, nearly identical to that shown in Figure 16 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.2±0.1°2-theta, 10.1±0.1°2-theta, 17.6±0.1°2-theta, 18.6±0.1°2-theta, 20.0±0.1°2-theta, 20.4±0.1°2-theta, 20.7±0.1°2-theta, 22.4±0.1°2-theta, 23.0±0.1°2-theta, 23.2±0.1°2-theta, 24.4±0.1°2-theta, 25.1±0.1°2-theta, 27.6±0.1°2-theta, and 29.3±0.1°2-theta; (c) Unit cell parameters at 100(2) K approximately equal to:

[0282] [Table 3]

[0283] Or, (d) combinations thereof.

[0284] In some embodiments, Form F of Compound 1 is characterized by having at least two of the properties selected from (a) through (c). In some embodiments, Form F of Compound 1 is characterized by having properties (a), (b), and (c).

[0285] In some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. In some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.2±0.1°2-theta, 10.1±0.1°2-theta, 17.6±0.1°2-theta, 18.6±0.1°2-theta, 20.0±0.1°2-theta, 20.4±0.1°2-theta, 20.7±0.1°2-theta, 22.4±0.1°2-theta, 23.0±0.1°2-theta, 23.2±0.1°2-theta, 24.4±0.1°2-theta, 25.1±0.1°2-theta, 27.6±0.1°2-theta, and 29.3±0.1°2-theta.

[0286] In some embodiments, Form F has unit cell parameters at 100(2) K approximately equal to:

[0287] [Table 4]

[0288] In some embodiments, Form F was obtained from methanol.

[0289] In some embodiments, Form F is solvated. In some embodiments, Form F is solvated with methanol.

[0290] <Preparation of Crystalline Forms> In some embodiments, a crystalline form of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is prepared as outlined in the Examples. Note that solvents, temperatures, and other reaction conditions presented herein may vary.

[0291] <Suitable solvent> Therapeutic drugs that can be administered to mammals, such as humans, must be prepared by following regulatory guidelines. Such government-regulated guidelines are called Good Manufacturing Practices (GMP). GMP guidelines address acceptable levels of contamination of active therapeutic agents, such as the amount of residual solvents in the final product. Preferred solvents are suitable for use in GMP facilities and are consistent with industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3)," (November 2005).

[0292] Solvents are classified into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents should be limited to use during the manufacture of therapeutic drugs. Class 3 solvents are considered less toxic and pose a lower risk to human health. Data on Class 3 solvents indicates that they are less toxic in acute or short-term studies and negative in genotoxicity tests.

[0293] Class 1 solvents to be avoided include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.

[0294] Examples of Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0295] Class 3 solvents with low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0296] Residual solvents in active pharmaceutical ingredients (APIs) result from the manufacturing of the APIs. In some cases, the solvents are not completely removed by the actual production techniques. The appropriate selection of solvents for the synthesis of APIs can enhance the yield or determine properties such as crystalline form, purity, and solubility. Therefore, the solvent is a critical parameter in the synthesis process.

[0297] In some embodiments, the composition comprising Compound 1 comprises an organic solvent. In some embodiments, the composition comprising Compound 1 comprises a balance of an organic solvent. In some embodiments, the composition comprising Compound 1 comprises a balance of a Class 3 solvent. In some embodiments, the active agent is a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0298] <Specific terminology> Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is understood that the foregoing general description and the following detailed description are exemplary and illustrative only and are not intended to limit any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is open-ended.

[0299] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, including but not limited to patents, patent applications, papers, books, manuals, and articles, are expressly incorporated herein by reference in their entirety for any purpose.

[0300] As used herein, the term "acceptable" or "pharmaceutically acceptable" with respect to a formulation, composition, or ingredient means that it has no lasting adverse effects on the general health of the treated subject or abrogates the biological activity or properties of the compound, and is relatively non-toxic.

[0301] As used herein, the term "agonist" refers to a compound, the presence of which results in a biological activity of a protein that is the same as the biological activity that results from the presence of a naturally occurring ligand for the protein, such as Btk.

[0302] As used herein, the term "partial agonist" refers to a compound, the presence of which results in the same type, but to a lesser extent, of biological activity of a protein that would result from the presence of a naturally occurring ligand for the protein.

[0303] As used herein, the term "antagonist" refers to a compound, the presence of which results in a decrease in the degree of biological activity of a protein. In certain embodiments, the presence of an antagonist results in complete inhibition of the biological activity of a protein, such as, for example, Btk. In certain embodiments, an antagonist is an inhibitor.

[0304] As used herein, "amelioration" of the symptoms of a particular disease, disorder, or condition by administering a particular compound or pharmaceutical composition refers to any permanent, temporary, long-term, or short-term decrease in severity, delay in onset, slowing of progression, or shortening of duration that may result from or be associated with the administration of the compound or composition.

[0305] "Bioavailability" refers to the percentage of administered Compound 1 that is delivered to the systemic circulation of the animal or human being studied. The total exposure (AUC (0-∞) ) is commonly defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which Compound 1 is absorbed into the systemic circulation when a pharmaceutical composition is obtained orally, as compared to intravenous injection.

[0306] "Plasma concentration" refers to the concentration of Compound 1 in the plasma component of a subject's blood. It is understood that due to variability in metabolism and / or possible interactions with other therapeutic agents, the plasma concentration of Compound 1 may vary significantly between subjects. In accordance with one embodiment disclosed herein, the plasma concentration of Compound 1 may vary from subject to subject. Similarly, the maximum plasma concentration (C max ) or time to maximum plasma concentration (T max ) or the area under the plasma concentration-time curve (AUC (0-∞) The total area under (a) may vary from subject to subject. Because of this variability, the amount necessary to constitute a "therapeutically effective amount" of Compound 1 may vary from subject to subject.

[0307] As used herein, the term "Bruton's tyrosine kinase" refers to Bruton's tyrosine kinase from Homo sapiens, as disclosed, for example, in U.S. Pat. No. 6,326,469 (GenBank Accession No. NP_000052).

[0308] As used herein, the term "Bruton's tyrosine kinase homolog" refers to an ortholog of Bruton's tyrosine kinase, e.g., an ortholog from mouse (GenBank Accession No. AAB47246), dog (GenBank Accession No. XP_549139), rat (GenBank Accession No. NP_001007799), chicken (GenBank Accession No. NP_989564), or zebrafish (GenBank Accession No. XP_698117), and a fusion protein of any of the foregoing that exhibits kinase activity toward one or more substrates of Bruton's tyrosine kinase (e.g., a peptide substrate having the amino acid sequence "AVLESEEELYSSARQ").

[0309] The term "co-administration" and the like, as used herein, is meant to encompass the administration of selected therapeutic agents to a single patient and is intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0310] The term "effective amount" or "therapeutically effective amount," as used herein, refers to a sufficient quantity of an administered drug or compound to relieve to some extent one or more symptoms of the disease or disorder being treated, resulting in a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, in therapeutic applications, an "effective amount" is the amount of a composition comprising a compound disclosed herein that is required to clinically sufficiently reduce disease symptoms without causing undue adverse side effects. An appropriate "effective amount" for any individual can be determined using techniques such as a dose escalation study. The term "therapeutically effective amount" includes, for example, an amount that is effective for prophylaxis. An "effective amount" of a compound disclosed herein is an amount that is effective to achieve a desired pharmacological effect or therapeutic improvement without causing undue adverse side effects. It is understood that an "effective amount" or "therapeutically effective amount" may vary from subject to subject, depending on variations in the metabolism of Compound 1, the subject's age, weight, general condition, the disorder being treated, the severity of the disorder being treated, and the judgment of the attending physician. By way of example only, a therapeutically effective amount may be determined by routine testing, including but not limited to, a dose escalation clinical trial.

[0311] The terms "enhance" or "enhancing" mean to increase or prolong, either in potency or duration, a desired effect. By way of example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong, either in potency or duration, the effect of the therapeutic agent during the treatment of a disease, disorder, or condition. As used herein, the term "enhancing-effective amount" refers to an amount adequate to enhance the effect of the therapeutic agent in treating a disease, disorder, or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0312] As used herein, the term "cognate cysteine" refers to a cysteine ​​residue found at a sequence position cognate to cysteine ​​481 of Bruton's tyrosine kinase, as defined herein. For example, cysteine ​​482 is the cognate cysteine ​​in the rat ortholog of Bruton's tyrosine kinase; cysteine ​​479 is the cognate cysteine ​​in the chicken ortholog; and cysteine ​​481 is the cognate cysteine ​​in the zebrafish ortholog. In another example, the cognate cysteine ​​in TXK, a member of the Tec kinase family related to the Bruton's tyrosine kinase, is cysteine ​​350. Other examples of kinases with cognate cysteines are shown in Figure 1. See also the sequence alignment of tyrosine kinases (TKs) published on the World Wide Web at kinase.com / human / kinome / phylogeny.html.

[0313] As used herein, the term "identical" refers to two or more sequences or subsequences that are the same. Furthermore, as used herein, the term "substantially identical" refers to two or more sequences that have a percentage of sequence units that are the same when compared and aligned for maximum correspondence over a comparison window, or over a specified region as measured using a comparison algorithm or by manual alignment and visual inspection. By way of example only, two or more sequences may be "substantially identical" if contiguous units are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region. Such percentages are intended to describe the "percent identity" of two or more sequences. Sequence identity can exist over a length of at least about 75-100 contiguous units, over a length of about 50 contiguous units, or, unless otherwise specified, over the entire sequence. This definition also refers to the complement of a test sequence. By way of example only, two or more polypeptide sequences are "substantially identical" if the amino acid residues are the same; or, two or more polypeptide sequences are "substantially identical" if the amino acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a designated region. Identity can exist over a region that is at least about 75-100 amino acids in length, a region that is about 50 amino acids in length, or, unless otherwise specified, over the entire polypeptide sequence. Additionally, by way of example only, two or more polynucleotide sequences are "substantially identical" if the nucleic acid residues are the same; or, two or more polynucleotide sequences are "substantially identical" if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a designated region. The identity can exist over a region that is at least about 75-100 nucleic acids in length, over a region that is about 50 nucleic acids in length, or, unless specified otherwise, over the entire sequence of the polynucleotide sequence.

[0314] As used herein, the terms "inhibit," "inhibiting," or "inhibitor," with respect to kinases, refer to the inhibition of the phosphotransferase activity of the enzyme.

[0315] As used herein, the term "irreversible inhibitor" refers to a compound that, after contact with a target protein (e.g., a kinase), causes the formation of a new covalent bond with or within the protein, whereby one or more of the biological activities of the target protein (e.g., phosphotransferase activity) are reduced or abolished despite the subsequent presence or absence of the irreversible inhibitor.

[0316] As used herein, the term "irreversible Btk inhibitor" refers to an inhibitor of Btk that can form a covalent bond with an amino acid residue of Btk. In one embodiment, an irreversible inhibitor of Btk can form a covalent bond with a cysteine ​​residue of Btk; in certain embodiments, an irreversible inhibitor can form a covalent bond with the cysteine ​​481 residue of Btk (or a homolog thereof) or a cysteine ​​residue at the corresponding position of a homolog of another tyrosine kinase.

[0317] As used herein, the term "isolated" refers to the separation and removal of a component of interest from components that are not of interest. Isolated materials can be in a dry or semi-dry state, or in a solution, including but not limited to, an aqueous solution. The isolated components can be in a homogenous state, or they can be part of a pharmaceutical composition that includes additional pharmaceutically acceptable carriers and / or excipients. By way of example only, a nucleic acid or protein is "isolated" when it is free of at least some of the cellular components that naturally accompany it, or when it is concentrated to a level higher than its in vivo or in vitro production. Also by way of example, a gene is isolated when it is separated from open reading frames that flank it and encode proteins other than the gene of interest.

[0318] The term "modulate," as used herein, means to interact directly or indirectly with a target to alter the activity of the target, which alteration of the activity of the target includes, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0319] As used herein, the term "modulator" refers to a compound that alters the activity of a molecule. For example, a modulator can cause an increase or decrease in the magnitude of a particular activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor that decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor is an inhibitor that completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator that increases the magnitude of one activity of a molecule. In certain embodiments, the presence of a modulator results in an activity that does not occur in the absence of the modulator.

[0320] As used herein, the term "prophylactically effective amount" refers to that amount of a composition applied to a patient which will relieve to some extent one or more of the symptoms of the disease, condition, or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's state of health, weight, and the like. It is well within the skill of one in the art for one to determine such prophylactically effective amounts by routine testing, including, but not limited to, dose escalation clinical trials.

[0321] As used herein, the term "subject" refers to an animal that has been the object of treatment, observation, or experiment. By way of example only, a subject may be a mammal, including, but not limited to, a human.

[0322] As used herein, the term "target activity" refers to a biological activity that can be modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or disorder.

[0323] As used herein, the term "target protein" refers to a protein molecule or portion that has the ability to be bound by a selective binding compound. In certain embodiments, the target protein is Btk.

[0324] The terms "treat," "treating," and "treatment," as used herein, include alleviating, reducing, or ameliorating the symptoms of a disease or condition, preventing further symptoms, ameliorating or preventing the underlying metabolic cause of a condition, inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, regressing a disease or condition, alleviating a condition caused by a disease or condition, or halting a disease or condition. The terms "treat," "treating," or "treatment" include, but are not limited to, prophylactic and / or therapeutic treatments.

[0325] As used herein, IC 50 refers to the amount, concentration, or dosage of a particular test compound that achieves 50% inhibition of a maximal response, such as inhibition of Btk, in an assay that measures the maximal response.

[0326] As used herein, EC 50 refers to the dose, concentration, or amount of a particular test compound that induces a dose-dependent response with 50% maximal expression of a particular response that is induced, caused, or potentiated by the particular test compound.

[0327] Pharmaceutical Compositions / Formulations

[0328] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Any of the well-known techniques, carriers, and excipients can be used as appropriate and as understood in the art. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entireties.

[0329] As used herein, a pharmaceutical composition refers to a mixture of Compound 1 containing other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening stabilizers, and / or excipients. A pharmaceutical composition facilitates administration of a compound to a mammal. In carrying out the treatment methods or uses provided herein, a therapeutically effective amount of a compound is administered as a pharmaceutical composition to a mammal having the disease, disorder, or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound can be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0330] The term "pharmaceutical combination," as used herein, refers to a product resulting from the mixing or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, e.g., Compound 1, and a co-agent are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., Compound 1, and a co-agent are administered to a patient as separate entities simultaneously, in parallel, or sequentially without a specific time limit between them, such that such administration provides the patient's body with effective levels of the two compounds. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0331] In some embodiments, crystalline Compound 1 is incorporated into a pharmaceutical composition to provide a solid oral dosage form. In other embodiments, crystalline Compound 1 is used to prepare a pharmaceutical composition other than an oral solid dosage form. The pharmaceutical formulations described herein are administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-dissolve formulations, tablets, capsules, pills, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multiparticulate formulations, and immediate-mix and controlled-release formulations.

[0332] Pharmaceutical compositions containing the compounds described herein may be manufactured in a conventional manner, such as by means of conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes, by way of example only.

[0333] <Dosage form> The pharmaceutical compositions described herein can be formulated for administration to a mammal via any conventional means, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject can be used interchangeably.

[0334] Furthermore, the pharmaceutical compositions described herein containing Compound 1 may be formulated into any suitable dosage form, including, but not limited to, solid oral dosage forms, controlled release formulations, fast dissolve formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0335] Oral pharmaceutical preparations can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally milling the resulting mixture, and processing the granular mixture, after adding suitable excipients, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or fillers such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrants can be added, such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate.

[0336] Orally usable pharmaceutical preparations include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient in a mixture with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0337] In some embodiments, the solid dosage forms disclosed herein can be in the form of a tablet (including a suspension tablet, a fast-dissolving tablet, a bite-disintegrating tablet, a quick-disintegrating tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (a soft or hard capsule, e.g., a capsule made from animal-derived gelatin or plant-derived HPMC, or a "sprinkle capsule"), a solid dispersion, a solid solution, a biodegradable dosage form, a controlled-release formulation, a pulsed-release dosage form, a multiparticulate dosage form, a pellet, a granule, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including, but not limited to, a fast-dissolving tablet. Additionally, the pharmaceutical formulations described herein can be administered as a single capsule or in a multi-capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, three, or four capsules or tablets.

[0338] In some embodiments, solid dosage forms (e.g., tablets, effervescent tablets, capsules) are prepared by blending particles of Compound 1 with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is meant that the particles of Compound 1 are evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. Individual unit dosage forms may also include a film coating that disintegrates after oral ingestion or contact with a diluent. These formulations may be manufactured by conventional pharmaceutical techniques.

[0339] Conventional pharmaceutical techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Worcester coating), tangential coating, top spraying, tabletting, extrusion, etc.

[0340] The pharmaceutical solid dosage forms described herein may comprise Compound 1 and one or more pharmaceutically acceptable excipients, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, transdermal absorption enhancer, humectant, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. In another aspect, a film coating is provided around a formulation of Compound 1 using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, some or all of the particles of Compound 1 are coated. In another embodiment, some or all of the particles of Compound 1 are microencapsulated. In another embodiment, the particles of Compound 1 are not microencapsulated or coated.

[0341] Carriers suitable for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0342] Fillers suitable for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0343] In order to release Compound 1 from the solid dosage form matrix as efficiently as possible, particularly when the dosage form is compressed with a binder, a disintegrant is often used in the formulation. Disintegrants help rupture the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Disintegrants suitable for use in solid dosage forms include, but are not limited to, natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, wood products, methyl crystalline cellulose (e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Min cross-linked celluloses such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, etc.In some embodiments provided herein, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked starches such as sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments provided herein, the disintegrant is croscarmellose sodium.

[0344] Binders impart cohesiveness to solid oral dosage form formulations: for powder-filled capsule formulations, they aid in clot formation, which may be filled into soft or hard shell capsules, and for tablet formulations, they ensure that the tablet remains intact after compression and help ensure blend uniformity before the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropyl methylcellulose acetate stearate (Aqoate Examples of suitable cellulose derivatives include cellulose acetate (HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, natural or synthetic gums such as acacia, tragacanth, ghatti gum, isapol husk mucilage, starch, polyvinylpyrrolidone (e.g., Povidone (isapol husk CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabinogalactan, Veegum®, polyethylene glycol, wax, sodium alginate, and the like.

[0345] Generally, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage levels in tablet formulations vary depending on whether the formulation is direct compression, wet granulation, roller compaction, or the use of other excipients such as fillers that may themselves act as moderate binders. While skilled formulators can determine the binder level for their formulations, binder usage levels of up to 70% in tablet formulations are common.

[0346] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax®, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium, or sodium lauryl sulfate. In some embodiments provided herein, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax. In some embodiments provided herein, the lubricant is magnesium stearate.

[0347] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, etc. In some embodiments provided herein, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrins, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, finely divided cellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

[0348] The term "water-insoluble diluent" includes pharmaceuticals such as calcium phosphate, calcium sulfate, starch, modified starch, and microcrystalline cellulose, and finely divided cellulose (e.g., about 0.45 g / cm 3 and is a powdered cellulose, e.g., Avicel, and represents compounds typically used in the formulation of talc.

[0349] Suitable moisturizers for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

[0350] Surfactants suitable for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF). In some embodiments provided herein, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

[0351] Suspending agents suitable for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30), polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to 6000, or about 3350 to 4000, or about 7000 to 5400), vinylpyrrolidone / vinyl copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ... Ingredients include cellulose, polysorbate 80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth, gum arabic, guar gum, xanthans including xanthan gum, sugars, celluloses (e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, etc.), polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0352] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0353] It should be understood that there is considerable overlap between the additives used in the solid dosage forms described herein. Thus, the additives listed above should be taken merely as representative, and not limiting, of the types of additives that may be included in the solid dosage forms described herein. The amounts of such additives can be readily determined by one skilled in the art according to the particular properties desired.

[0354] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, plasticizers are generally high-boiling solids or liquids. Suitable plasticizers may be added in amounts ranging from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0355] Compressed tablets are solid dosage forms prepared by compressing a bulk blend of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth contain one or more flavorings. In other embodiments, compressed tablets contain a film surrounding the final compressed tablet. In some embodiments, the film coating can provide delayed release of the compound from the formulation. In other embodiments, the film coating aids patient compliance (e.g., Opadry® coating, or sugar coating). Film coatings, including Opadry®, typically range from about 1% to about 3% of the tablet weight. In other embodiments, compressed tablets contain one or more excipients.

[0356] Capsules can be prepared, for example, by placing a bulk blend of a Compound 1 formulation inside a capsule. In some embodiments, the formulation (non-aqueous suspensions and solutions) is placed in a soft gelatin capsule. In other embodiments, the formulation is placed in a standard gelatin capsule or a non-gelatin capsule, such as a capsule containing HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, where the capsule can be swallowed whole, or the capsule can be opened and the contents sprinkled on food before a meal. In some embodiments, a therapeutic dose is divided into multiple (e.g., 2, 3, or 4) capsules. In some embodiments, the entire dose of the formulation is delivered in capsule form.

[0357] In various embodiments, particles of Compound 1 and one or more excipients are dry mixed and compressed into a mass, such as a tablet, that has sufficient hardness to provide a pharmaceutical composition that substantially disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation into gastrointestinal fluids.

[0358] In another aspect, the dosage form may comprise a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, humectants, and diluents.

[0359] Materials useful for microencapsulation as described herein include materials compatible with Compound 1 that sufficiently separate Compound 1 from other incompatible excipients. Materials compatible with Compound 1 are those that delay the release of Compound 1 in vivo.

[0360] Exemplary microencapsulation materials useful for delaying the release of formulations comprising the compounds described herein include, but are not limited to, hydroxypropyl cellulose ethers (HPC), such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methylcellulose ethers (HPMC), such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers, such as Methocel®-A, hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS), and Metolose®, ethylcellulose (EC) and mixtures thereof, such as E461, Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA), such as Opadry®. AMB, hydroxyethylcellulose, such as Natrosol®, carboxymethylcellulose (CMC), such as Aqualon®-CMC, polyvinyl alcohol, and polyethylene glycol copolymers, such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers, such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE 30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrin, and mixtures of these materials.

[0361] In yet other embodiments, plasticizers such as polyethylene glycol (e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, PEG 800), stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulation material useful for delaying the release of the pharmaceutical composition is from the USP or National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In yet other embodiments, the microencapsulation material is methocel.

[0362] Microencapsulated Compound 1 can be formulated by methods known to those skilled in the art. Such known methods include, for example, spray drying, spin-disk dissolution processing, hot-melt processing, spray-chilling, fluidized bed, electrostatic deposition, centrifugal drainage, rotary suspension separation, polymerization at a liquid-gas or solid-gas interface, pressure drainage, or spray-solvent extraction. In addition, various chemical techniques, such as complex coacervation, melt evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, submerged drying, and desolvation in liquid media, can also be used. Furthermore, other methods, such as roller compaction, drainage / spheronization, coacervation, or nanoparticle coating, can also be used.

[0363] In one embodiment, particles of Compound 1 are microencapsulated before being formulated into one of the above forms, hi yet another embodiment, some or most of the particles are coated before being further formulated by using standard coating procedures (such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000)).

[0364] In another embodiment, the solid dosage formulation of Compound 1 is plasticized (coated) with one or more layers. Illustratively, plasticizers are generally high-boiling solids or liquids. Suitable plasticizers can be added in amounts ranging from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0365] In other embodiments, powders containing formulations with Compound 1 can be formulated to include one or more pharmaceutical excipients and flavoring agents. Such powders can be formulated, for example, by mixing the formulation and any pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and / or a humectant. This bulk blend is then uniformly subdivided into unit dosage packages or multi-dose packages.

[0366] In yet another embodiment, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse medications in water for oral administration. Effervescent salts are granules or coarse powders containing a drug in a dry mixture, typically composed of sodium bicarbonate, citric acid, and / or tartaric acid. When the salts of the compositions described herein are added to water, the acid and base react to liberate carbon dioxide, thereby causing "effervescence." Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate, or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate, citric acid, and tartaric acid, as long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or greater.

[0367] In some embodiments, the solid dosage forms described herein can be formulated as enteric-coated delayed-release oral dosage forms, i.e., oral dosage forms of pharmaceutical compositions as described herein that utilize an enteric coating to affect release in the small intestine of the gastrointestinal tract. Enteric-coated dosage forms can be compressed, molded, or extruded tablets / features (coated or uncoated) containing granules, powders, pellets, beads, or microparticles of the active ingredient and / or other compositional components (themselves coated or uncoated). Enteric-coated dosage forms can also be capsules (coated or uncoated) and / or compositions (themselves coated or uncoated) containing granules, powders, pellets, beads, or microparticles of a solid carrier.

[0368] As used herein, the term "delayed release" refers to delivery such that release can be achieved at some generally predictable location in the gastrointestinal tract further distally than would be achieved in the absence of delayed release modifications. In some embodiments, the method of delayed release is a coating. Any coating must be applied to a sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, but dissolves at a pH above about 5. It is anticipated that any anionic polymer that exhibits pH-dependent solubility properties can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, the polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to, the following:

[0369] Shellac, also known as purified lac, is a refined product obtained from the resinous secretions of insects. This coating dissolves in media with a pH greater than 7;

[0370] Acrylic polymers. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available solubilized in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but permeable and are primarily used for colonic targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach and dissolve in the intestine;

[0371] Cellulose derivatives. Examples of suitable cellulose derivatives include: ethyl cellulose; a reaction mixture of a partial acetate ester of cellulose with phthalic anhydride. Performance may vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH >6. Aquateric (FMC) is an aqueous-based system and is a spray-dried CAP pseudolatex with particles <1 μm. Other components in Aquateric may include pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). Performance may vary based on the degree and type of substitution. For example, HPMCP (such as grades HP-50, HP-55, HP-55S, and HP-55F) is suitable. Performance may vary based on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include AS-LG (LF), which dissolves at pH 5; AS-MG (MF), which dissolves at pH 5.5; and AS-HG (HF), which dissolves at higher pHs. These polymers are available as granules or aqueous dispersions; fine powders for polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH >5, and it is poorly permeable to water vapor and gastric juices.

[0372] In some embodiments, the coating may contain, or typically contains, a plasticizer and other coating excipients known in the art, such as colorants, talc, and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers typically contain 10-25% by weight of a plasticizer, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques, such as spray or pan coating, are utilized to apply the coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the gastric tract is reached.

[0373] Colorants, detackifiers, surfactants, antifoaming agents, lubricants (e.g., carnuba wax or PEG) may be added to the coating in addition to plasticizers to solubilize or disperse the coating materials and to improve coating performance and the coated product.

[0374] In other embodiments, the formulations described herein containing Compound 1 are delivered using a pulsatile dosage form. Pulsatile dosage forms can provide one or more immediate-release pulses at predetermined times or at specific sites after a controlled lag time. Many other types of controlled-release systems known to those skilled in the art are suitable for use with the formulations described herein. Examples of such delivery systems include polymer-based systems such as polylactic acid and polyglycolic acid, polyanhydrides, and polycaprolactone; porous matrices, non-polymer-based systems, such as lipids containing sterols (e.g., cholesterol, cholesterol esters, and fatty acids, or neutral lipids (monoglycerides, diglycerides, and triglycerides)); hydrogel release systems; silastic systems; peptide-based systems; compressed tablets using wax coatings, biodegradable dosage forms, conventional binders, etc. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2nd Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 751-753 (2002); U.S. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983, each of which is specifically incorporated by reference.

[0375] In some embodiments, a pharmaceutical formulation is provided for oral administration to a subject, comprising particles of Compound 1 and at least one dispersing or suspending agent. The formulation may be a powder and / or granules for suspension, which upon mixing with water results in a substantially uniform suspension.

[0376] It is understood that there is overlap among the above-listed additives used in the aqueous dispersions or suspensions described herein, as a given additive is often classified differently by different practitioners in the art or is commonly used for a variety of different functions. Therefore, the above-listed additives should be taken merely as representative and, without limitation, as types of additives that may be included in the formulations described herein. The amounts of such additives can be readily determined by those skilled in the art according to the specific properties desired.

[0377] Medication and Treatment Regimen In some embodiments, the amount of Compound 1 administered to the mammal is from 300 mg / day to 1000 mg / day. In some embodiments, the amount of Compound 1 administered to the mammal is from 420 mg / day to 840 mg / day. In some embodiments, the amount of Compound 1 administered to the mammal is about 420 mg / day, about 560 mg / day, or about 840 mg / day. In some embodiments, the amount of Compound 1 administered to the mammal is about 420 mg / day. In some embodiments, the amount of Compound 1 administered to the mammal is about 560 mg / day. In some embodiments, the AUC of Compound 1 0-24 is about 150 and about 3500ng * h / mL. In some embodiments, the AUC 0-24 is about 500 and about 1100ng * h / mL. In some embodiments, Compound 1 is administered orally. In some embodiments, Compound 1 is administered once per day, twice per day, or three times per day. In some embodiments, Compound 1 is administered daily. In some embodiments, Compound 1 is administered once per day. In some embodiments, Compound 1 is administered every other day. In some embodiments, Compound 1 is a maintenance therapy.

[0378] Compound 1 can also be used in the preparation of a medicament for the inhibition of Btk or a homolog thereof, or for the treatment of a disease or disorder that would benefit, at least in part, from the inhibition of Btk or a homolog thereof, including subjects diagnosed with a hematological malignancy. Additionally, methods for treating any of the diseases or disorders described herein in a subject in need of such treatment include administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

[0379] Compositions comprising Compound 1 can be administered for prophylactic, therapeutic, or maintenance treatments. In some embodiments, compositions comprising Compound 1 are administered for therapeutic purposes (e.g., to a subject diagnosed with a hematologic malignancy). In some embodiments, compositions comprising Compound 1 are administered for therapeutic purposes (e.g., to a subject suspected of or at risk of developing a hematologic malignancy). In some embodiments, compositions comprising Compound 1 are administered to patients in remission as maintenance therapy.

[0380] The amount of Compound 1 depends on the use (e.g., therapeutic, prophylactic, or maintenance). The amount of Compound 1 will depend on the severity and course of the disease or condition, previous treatments, the patient's health, weight, and responsiveness to the drug, and the judgment of the treating physician. Determining such therapeutically effective amounts by periodic testing (including, but not limited to, dose escalation clinical trials) is well within the skill of one in the art. In some embodiments, the amount of Compound 1 is from 300 mg / day to 1000 mg / day. In some embodiments, the amount of Compound 1 is from 420 mg / day to 840 mg / day. In some embodiments, the amount of Compound 1 is from 400 mg / day to 860 mg / day. In some embodiments, the amount of Compound 1 is about 360 mg / day. In some embodiments, the amount of Compound 1 is about 420 mg / day. In some embodiments, the amount of Compound 1 is about 560 mg / day. In some embodiments, the amount of Compound 1 is about 840 mg / day. In some embodiments, the amount of Compound 1 is from 2 mg / kg / day to 13 mg / kg / day. In some embodiments, the amount of Compound 1 is from 2.5 mg / kg / day to 8 mg / kg / day. In some embodiments, the amount of Compound 1 is from 2.5 mg / kg / day to 6 mg / kg / day. In some embodiments, the amount of Compound 1 is from 2.5 mg / kg / day to 4 mg / kg / day. In some embodiments, the amount of Compound 1 is about 2.5 mg / kg / day. In some embodiments, the amount of Compound 1 is about 8 mg / kg / day.

[0381] In some embodiments, the pharmaceutical compositions described herein contain about 140 mg of Compound 1. In some embodiments, a capsule formulation containing about 140 mg of Compound 1 is prepared. In some embodiments, two, three, four, or five capsule formulations are administered daily. In some embodiments, three or four capsules are administered daily. In some embodiments, three 140 mg capsules are administered once daily. In some embodiments, four 140 mg capsules are administered once daily. In some embodiments, a capsule is administered once daily. In other embodiments, a capsule is administered multiple times per day.

[0382] In some embodiments, Compound 1 is administered daily. In some embodiments, Compound 1 is administered every other day.

[0383] In some embodiments, Compound 1 is administered once per day. In some embodiments, Compound 1 is administered twice per day. In some embodiments, Compound 1 is administered three times per day. In some embodiments, Compound 1 is administered four times per day.

[0384] In some embodiments, Compound 1 is administered until disease progression, unacceptable toxicity, or personal choice. In some embodiments, Compound 1 is administered daily until disease progression, unacceptable toxicity, or personal choice. In some embodiments, Compound 1 is administered every other day until disease progression, unacceptable toxicity, or personal choice.

[0385] Alternatively, the administered dose of the drug may be temporarily reduced or temporarily discontinued for a specified period (drug holiday). The length of the drug holiday may vary between 2 days and 1 year (including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days). Dose reductions during drug holidays can be 10%-100% (including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%).

[0386] Once improvement of the patient's disease has occurred, a maintenance dose is administered if necessary. The dosage or frequency of administration, or both, may then be reduced, depending on the symptoms, to a level that sustains improvement of the disease, disorder, or condition. However, patients may require intermittent treatment on a long-term basis following any recurrence of symptoms.

[0387] The amount of a given agent corresponding to such an amount will vary depending on factors such as the particular compound, the severity of the disease, the identity (e.g., body weight) of the subject or host in need of treatment, and the like, but may nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, and the subject or host being treated. In general, however, dosages utilized for adult human treatment will typically be in the range of 0.02-5000 mg per day, or 1-1500 mg per day. The desired dosage may conveniently be provided in a single dose, or in divided doses administered simultaneously (or over a short period of time), or as sub-doses administered at appropriate intervals, e.g., two, three, four, or more times daily.

[0388] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise dosage amounts. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dosage is in the form of a package containing discrete amounts of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is common to include a preservative in the composition. By way of example only, formulations for parenteral injection may be provided in unit dosage form, including, but not limited to, ampoules, or in multi-dose containers with an added preservative. In some embodiments, each unit dosage form contains 140 mg of Compound 1. In some embodiments, an individual is administered one unit dosage form per day. In some embodiments, an individual is administered two unit dosage forms per day. In some embodiments, an individual is administered three unit dosage forms per day. In some embodiments, an individual is administered four unit dosage forms per day.

[0389] Because of the large number of variables associated with particular treatment regimens, the foregoing ranges are only suggestive, and considerable variation from these recommendations is not uncommon. Such dosages may vary depending on many variables, including, but not limited to, the activity of the compound being used, the disease or condition being treated, the mode of administration, the requirements of the particular subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0390] The toxicity and therapeutic efficacy of such treatment regimens are 50 (50% lethal dose in the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and is known as the LD 50 and ED 50The therapeutic index may be expressed as a ratio between ED and ED . Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies may be used to formulate a range of dosages for use in humans. The dose of such compounds is preferably adjusted to achieve the ED with minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form and route of administration utilized.

[0391] <Combination therapy> In certain instances, it will be appropriate to administer Compound 1 in combination with another therapeutic agent.

[0392] In one embodiment, the compositions and methods described herein are also used in combination with other therapeutic agents selected for their specific usefulness against the disease being treated. Generally, the compositions described herein and in embodiments in which combination therapy is used, other agents, need not be administered in the same pharmaceutical composition, nor by different routes due to different physical and chemical characteristics. In one embodiment, initial administration is performed according to an established protocol, with subsequent modifications to dosage, method of administration, and frequency of administration based on observed effects.

[0393] In various embodiments, the compounds are administered simultaneously (e.g., simultaneously, nearly simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, the patient's illness, and the actual choice of compounds used. In certain embodiments, the determination of the order of administration during a treatment protocol, and the order and number of repetitions of administration of each therapeutic agent during a treatment procedure, is based on an assessment of the disease being treated and an assessment of the patient's condition.

[0394] With respect to the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug being utilized, the particular drug being utilized, the disease or disorder being treated, and the like.

[0395] The individual compounds of such combinations may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds are administered simultaneously in a combined pharmaceutical formulation. Appropriate doses of known therapeutic agents can be assessed by those skilled in the art.

[0396] The combinations referred to herein may conveniently be presented for use in the form of a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier.

[0397] Disclosed herein, in certain embodiments, are methods of treating cancer in an individual in need thereof, the methods comprising administering to the individual an amount of Compound 1. In some embodiments, the methods further comprise administering a second cancer treatment regimen.

[0398] In some embodiments, administration of a Btk inhibitor before a second cancer treatment regimen reduces an immune-mediated response to the second cancer treatment regimen. In some embodiments, administration of Compound 1 before ofatumumab reduces an immune-mediated response to ofatumumab.

[0399] In some embodiments, the second cancer treatment regimen comprises a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted therapy, or a combination thereof. In some embodiments, the second cancer treatment regimen comprises a B cell receptor pathway inhibitor. In some embodiments, the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blk inhibitor, a PLCγ inhibitor, a PKCβ inhibitor, or a combination thereof. In some embodiments, the second cancer treatment regimen is an antibody, a B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a radioimmunotherapeutic, a DNA damaging agent, a proteosome inhibitor, a Cyp3A4 inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jak1 / 2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.

[0400] In some embodiments, the second cancer treatment regimen comprises chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.

[0401] In some embodiments, the second cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally, rituximab.

[0402] In some embodiments, the second cancer treatment regimen comprises bendamustine and rituximab.

[0403] In some embodiments, the second cancer treatment regimen comprises fludarabine, cyclophosphamide, and rituximab.

[0404] In some embodiments, the second cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone, and optionally, rituximab.

[0405] In some embodiments, the second cancer treatment regimen comprises etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and, optionally, rituximab.

[0406] In some embodiments, the second cancer treatment regimen comprises dexamethasone and lenalidomide.

[0407] In some embodiments, the second cancer treatment comprises a proteasome inhibitor. In some embodiments, the second treatment comprises bortezomib. In some embodiments, the second cancer treatment comprises an epoxyketone. In some embodiments, the second cancer treatment comprises epoxomicin. In some embodiments, the second cancer treatment comprises a tetrapeptide epoxyketone. In some embodiments, the second cancer treatment comprises carfilzomib. In some embodiments, the second cancer treatment comprises disulfuram, epigallocatechin-3-gallate, salinosporamide A, ONX 0912m CEP-18770, MLN9708, or MG132.

[0408] In some embodiments, the second cancer treatment comprises a Cyp3A4 inhibitor. In some embodiments, the second cancer treatment comprises indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone. In some embodiments, the second cancer treatment comprises ketoconazole.

[0409] In some embodiments, the second cancer treatment comprises a Janus kinase (JAK) inhibitor, hi some embodiments, the second treatment comprises lestaurtinib, tofacitinib, ruxolitinib, CYT387, barititinib, or pacritinib.

[0410] In some embodiments, the second cancer treatment comprises a histone deacetylase inhibitor (HDAC inhibitor, HDI). In some embodiments, the second cancer treatment comprises a hydroxamic acid (or hydroxamate) such as trichostatin A, vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat (LBH589), a cyclic tetrapeptide such as trapoxin B, depsipeptide, a benzamide such as entinostat (MS-275), CI994, and mocetinostat (MGCD0103), an electrophilic ketone, or a fatty acid compound such as phenylbutyrate, and valproic acid.

[0411] Additional cancer treatment regimens include, for example, nitrogen mustards such as bendamustine, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, prednimustine, and tofosfamide; alkyl sulfonates such as busulfan, mannosulfan, and treosulfan; ethyleneimines such as carboquone, thiotepa, and triaziquone; nitrosoureas such as carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, and streptozocin; and epothiones such as etoglucan. other alkylating agents, such as dacarbazine, mitobronitol, pipobroman, and temozolomide; folic acid analogs, such as methotrexate, pemetrexed, pralatrexate, and raltitrexed; purine analogs, such as cladribine, clofarabine, fludarabine, mercaptopurine, nelarabine, and thioguanine; pyrimidine analogs, such as azacitidine, capecitabine, carmofur, cytarabine, decitabine, fluorouracil, gemcitabine, and tegafur. vinca alkaloids, such as vinblastine, vincristine, vindesine, vinflunine, vinorelbine; podophyllotoxin derivatives, such as etoposide etoglucide; colchicine derivatives, such as demecolcine; taxanes, such as docetaxel, paclitaxel, paclitaxel poliglumex; other plant alkaloids and natural products, such as trabectedin; actinomycins, such as dactinomycin; aclarubicin, daunorubicin, doxorubicin, epirubicin, ibuprofen anthracyclines such as darubicin, mitoxantrone, pirarubicin, valrubicin, and zorubicin; other cytotoxic antibiotics such as bleomycin, ixabepilone, mitomycin, and temozolomide; platinum compounds such as carboplatin, cisplatin, oxaliplatin, and satraplatin; methylhydrazines such as procarbazine; sensitizers such as aminolevulinic acid, efaproxiral, methyl aminolevulinate, porfimer sodium, and temoporfin;Protein kinase inhibitors such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, and temsirolimus; protein kinase inhibitors such as alitretinoin, altretamine, amzacrine, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, denileukin diftitox, estramustine, hydroxycarbamide, and irinotecan. Other antineoplastic agents such as lonidamine, masoprocol, miltefosine, mitoguazone, mitotane, oblimersen, pegaspargase, pentostatin, romidepsin, sitimagine seradenovec, tiazofurin, topotecan, tretinoin, and vorinostat; estrogens such as diethylstilbenol, ethinyl estradiol, fosfestrol, and polyestradiol phosphate; progestogens such as roxyprogesterone and megestrol; gonadotropin-releasing hormone analogues such as buserelin, goserelin, leuprorelin, and triptorelin; antiestrogens such as fulvestrant, tamoxifen, and toremifene; antiandrogens such as bicalutamide, flutamide, nilutamide, enzyme inhibitors, aminoglutethimide, anastrozole, exemestane, formestane, letrozole, and vorozole; and anticoagulants such as abarelix and degarelix. any other antihormonal substance; immunostimulants such as histamine dihydrochloride, mifamurtide, pidotimod, plerixafor, roquinimex, thymopentin, etc.; immunosuppressants such as everolimus, gusperimus, leflunomide, mycophenolate, sirolimus, etc.; calcineurin inhibitors such as cyclosporine, tacrolimus, etc.; other immunosuppressants such as azathioprine, ixabepilone, methotrexate, thalidomide, etc.; and radiopharmaceuticals such as iobenguane, etc.

[0412] Additional cancer treatment regimens include interferons, interleukins, tumor necrosis factors, growth factors, and the like.

[0413] Additional cancer treatment regimens include immunostimulants such as ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, and sargramostim; interferons such as natural interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon alfacon-1, interferon alpha-n1, natural interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, pegylated interferon alpha-2a, and pegylated interferon alpha-2b; interleukins such as aldesleukin and oprelvekin; and anti-cancer drugs such as BCG vaccine, glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor, poly I:C, poly ICLC, and roxinime. other immunostimulants such as acetaminophen, tasonermin, thymopentin; immunosuppressants such as abatacept, abetimus, alefacept, antilymphoid immunoglobulin (horse), antithymocyte immunoglobulin (rabbit), eculizumab, efalizumab, everolimus, gusperimus, leflunomide, muromab-CD3 mycophenolate, natalizumab, sirolimus; TNF-alpha inhibitors such as lutolizumab pegol, etanercept, golimumab, infliximab; interleukin inhibitors such as anakinra, basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept, tocilizumab, ustekinumab; calcineurin inhibitors such as cyclosporine, tacrolimus; and other immunosuppressants such as azathioprine, lenalidomide, methotrexate, thalidomide.

[0414] Additional cancer treatment regimens include adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, ibritumomab tiuxetan, infliximab, muromonab-CD3, natalizumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab, or combinations thereof.

[0415] Additional cancer treatment regimens include, for example, alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab, trastuzumab, immunosuppressants, monoclonal antibodies such as eculizumab, efalizumab, muromab-CD3, natalizumab; interleukin inhibitors, for example, adalimumab, afelimomab, certolizumab pegol, golimumab, infliximab, interleukin inhibitors, basiliximab, canakinumab, daclizumab, mepolizumab, tocilizumab; TNF-alpha inhibitors such as tetanus, ustekinumab, radiopharmaceuticals, ibritumomab tiuxetan, and tositumomab; abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab, arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab, brentuximab vedotin, capromab pendetide, and cixutumumab. Claudiximab, conatumumab, dacetuzumab, denosumab, eculizumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab, ganitumab, gemtuzumab ozogamicin, glevatumumab, ibritumomab, ibritumomab ozogamicin, ipilimumab, lexatumumab, lintuzumab, lintuzumab, lucatumumab Other monoclonal antibodies include rifabutinib, pamatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, necitumumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab, ramacurimab, ranibizumab, siplizumab, sonepcizumab, tanezumab, tositumomab, trastuzumab, tremelimumab, tucotuzumab, celmoleukin, veltuzumab, visilizumab, volociximab, and zalutumumab.

[0416] Additional cancer treatment regimens include agents that affect the tumor microenvironment, such as cellular signaling networks (e.g., phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling from B cell receptors, and IgE receptors). In some embodiments, the second agent is a PI3K signaling inhibitor or a syc kinase inhibitor. In one embodiment, the syk inhibitor is R788. In another embodiment, the PKCγ inhibitor is, by way of example only, enzastaurin.

[0417] Examples of drugs that affect the tumor microenvironment include PI3K signaling inhibitors, syc kinase inhibitors, protein kinase inhibitors such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, and temsirolimus; other angiogenesis inhibitors such as GT-111, JI-101, and R1530; and other angiogenesis inhibitors such as AC220, AC480, ACE-041, AMG 900, AP24534, Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762, AZD8055, AZD8931, bafetinib, BAY73-4506, BGJ398, BGT226, and BI 811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036, dinaciclib, dovitinib lactate, E7050, EMD1214063, ENMD-2076, fostamatinib Thorium, GSK2256098, GSK690693, INCB18424, INNO-406, JNJ-26483327, JX-594, KX2-391, linifanib, LY2603618, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON 01919.Na, OSI-027, OSI-930 Other kinase inhibitors include Btk inhibitors, PF-00562271, PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502, PF-3758309, PHA-739358, PLC3397, progenipoietin, R547, R763, ramucirumab, regorafenib, RO5185426, SAR103168, SCH727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN-232, TTP607, XL147, XL228, XL281, RO5126766, XL418, XL765.

[0418] Further examples of anti-cancer agents for use in combination with the Btk inhibitor compounds include inhibitors of mitogen-activated protein kinase signaling, such as U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., Rituxan).

[0419] Other anticancer drugs that may be utilized in combination with Btk inhibitor compounds include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacytidine; azetepa; aztomycin; batimastat; benzodepa; bicalutamide; acodazole hydrochloride; bian Bisnafide dimesylate; Biceresin; Bleomycin sulfate; Brequinar sodium; Bropirimine; Busulfan; Cactinomycin; Calsterone; Caracemide; Carvetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelcin; Cedefingal; Chlorambucil; Ciloremycin; Cladribine; Crisnatol mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin hydrochloride; Decitabine; Dextromaplatin; Dezaguamine; Dezaguamine mesylate; Diazicon; Doxorubicin Doxorubicin hydrochloride;Droloxifene;Droloxifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;Elsamitrucin;Enloplatin;Empromate;Epipropizine;Epirubicin hydrochloride;Elbrozole;Esorubicin hydrochloride;Estramustine;Estramustine sodium phosphate;Etanidazole;Etoposide;Etoposide phosphate;Etoprine;Fadrozole hydrochloride;Fazarabine;Fenretinide;Floxuridine;Fludarabine phosphate;Fluorouracil;Flu Ilocitabine; Fosquidan; Fostriecin sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Imofostin; Interleukin II (including recombinant interleukin II, or rlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-la; interferon gamma-lb; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole;Leuprolide acetate; Liarozole hydrochloride; Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Merenguethrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcin; Mitochromin; Mitoziline; Mitomarcin; Mitomycin; Mitospel; Mitotane ;Mitoxantrone hydrochloride;Mycophenolic acid;Nocodazoi;Nogalamycin;Ormaplatin;Oxislan;Pegaspargase;Periomycin;Pentamastine;Peplomycin sulfate;Perfosfamide;Pipobroman;Piposulfan;Piroxantrone hydrochloride;Plicamycin;Promestane;Porfimer sodium;Porfiromycin;Prednimastine;Procarbazine hydrochloride;Puromycin;Puromycin hydrochloride;Pirazofurin;Riboprin;Rogletimide;Sa Fingal; Safingal hydrochloride; Semustine; Simtrazene; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromastine; Spiroplatin; Streptonigrin; Streptozocin; Surofenal; Tallysomycin; Tecogalan sodium; Tegafur; Trexatron hydrochloride; Temoporfin; Teniposide; Teloxylon; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Toremifeniferum citrate threstrone acetate; tricibirine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tuburozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglisinate sulfate; vinleurodine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzoquidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride;

[0420] Other anticancer agents that may be utilized in combination with Btk inhibitor compounds include: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; akylfulvene; adecipenol; adzelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamastine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1 (anti-TK antagonist). protein-1); antiandrogens, prostate cancer; antiestrogens; antineoplastons; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; cell death regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulaculin; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxins; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL Antagonists;Benzotyroline;Benzoylstaurosporine;Beta-lactam derivatives;Beta-arretin;Betaclamycin B;Betulinic acid;bFGF inhibitors;Bicalutamide;Bisantrene;Visaziridinylspermine;Biansafide;Bistraten A;Biceresin;Brefurate;Bropirimine;Budotitanium;Buthionine sulfoximine;Calcpotriol;Calfostin C;Camptothecin derivatives;Canaripox IL-2;Capecitabine;Carboxamido-amino-triazoles;Carboxamidotriazoles;CaRest M3; CARN 700; Cartilage-derived inhibitor; Carzelcin; Casein kinase inhibitor (ICOS); Castanospermine; Cecropin B; Cetrorelix; Chlorin; Chloroquinoxaline sulfonamide; Cicaprost; cis-Porphyrin; Cladribine; Clomiphene analogs; Clotrimazole; Collismycin A; Collismycin B; Combretastatin A4; Combretastatin analogs; Conagenin;Crambescidin 816; Crisnatol; Cryptophycin 8; Cryptophycin A derivatives; Curacin A; Cyclopentylchinoside; Cycloplatam; Sipemycin; Cytarabine ocfosfate; Cytotoxic factors; Cytostatin; Daclizumab; Decitabine; Dehydrodidemin B; Deslorelin; Dexamethasone; Dexfosdamide; Dexrazoxane; Dexverapamil; Diazicon; Didemin B; Didox; Diethylnorspermine; Dihydro-5-azacytidine; 9-dioxamycin; Diphen Nilspiromastine; Docosanol; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; Duocarmycin SA; Ebselen; Ecomustine; Edelfostine; Edrecolomab; Eflornithine; Elemene; Emitefur; Epirubicin; Epristeride; Estramustine analogs; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide phosphate; Exemestane; Fadrozole; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopiridol; Fretu Elastin; Fluasterone; Fludarabine; Fluorodaunornithine Hydrochloride; Forfenimex; Formestane; Fostriecin; Fotemustine; Gadolinium texapyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitors; Gemcitabine; Glutathione inhibitors; Hapsulfame; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Idramantone; Ilmofosine; Ilmostat; Imidazoacridone; Imiquimod ;Immunostimulant peptides;Insulin (e.g., growth factor-1 receptor inhibitors, etc.);Interferon agonists;Interferons;Interleukins;Iobenguane;Iododoxorubicin;Ipomeanol, 4-;Ilopract;Irsogladine;Isobengazole;Isohomohalichondrin B;Itasetron;Jasplakinolide;Kahalalide F;Lamellarin-N triacetate;Lanreotide;Leinamycin;Lenograstim;Lentinan sulfate;Leptolstatin;Letrozole;Leukemia inhibitory factor;Leukocyte alpha interferon;Leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide; lobaplatin; lombricin; lometerexol; lonidamine; losoxantrone; lovastatin; loxolibine; raltotecan; lutetium texapyrrin; lisofylline; cytolytic peptides; maytansine; mannostatin A; marimastat; massoprocol; maspin; matrilysin inhibitors; matrix metalloproteinases teinase inhibitors; menogaril; melbarone; metalelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; millimostim; incorrect double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofalotene; molgramostim; monoclonal antibodies (human placental gonadotropin); monophosphoryl lipid A + myobacterial cell wall sk; mopidamol; multidrug resistance gene inhibitors; multiple tumor suppressor gene 1-based Treatment; Mustard anticancer drugs; Mycaperoxide B; Mycobacterial cell wall extract; Mirapolon; n-acetyldinaline; N-substituted benzamides; Nafarelin; Nagrestip; Naloxone + pentazocine; Napavine; Naphtharpine; Nartograstim; Nedaplatin; Nemorubicin; Nilidronic acid; Neutral endopeptidase; Nilutamide; Nisamycin; Nitric oxide modulators; Nitroxide antioxidants; Nitrulline; O6-benzylguanine; Octreotide; Oxenone; Oligonucleotides; Onapristone; Ondansetron; On Dansetron; Oracin; Oral cytokinin inducers; Ormaplatin; Osateron; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylrhizoxin; Pamidronate; Panaxytriol; Panomyphen; Parabactin; Pazeliptin; Pegaspargase; Perdecin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron; Perfosfamide; Peril alcohol; Phenazinomycin; Phenyl acetate; Phosphatase inhibitors; Picibanil; Pilocarpine hydrochloride; Pirarubicin;Piritrexim; Withaferin A; Prasetin B; Plasminogen activator inhibitors; Platinum complexes; Platinum compounds; Platinum triamine complexes; Porfimer sodium; Porfiromycin; Prednisone; Propylbis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A-based immunomodulators; Protein kinase C inhibitors; Protein kinase C inhibitors, microalgae; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Purpurin; Pyrazoloacridine; Pyridoxylated hemoglobin poloxyethyl erie conjugate; RAF antagonists; Raltitrexed; Ramosetron; Ras farnesyl protein transferase inhibitors; Ras inhibitors; Ras-GAP inhibitors; Demethylated retiptin; Rhenium Re 186 Etidronate; Rhizoxin; Ribozyme; RII retinamide; Rogletimide; Rohitukin; Romurtide; Roquinimex; Ravidinone B1; Lavoxil; Safingal; Saintopin; SarCNU; Sarcophytol A; Sargramostim; Sdi 1 mimetic; Semustine; Senescense-derived inhibitor 1; Sense oligonucleotide; Signal transduction inhibitor; Signal transduction modulator; Single-chain antigen binding protein; Sizofiran; Sobuzoxane; Sodium borocaptate; Sodium phenylacetate; Salvalor; Somatomedin-binding protein; Sonarmin; Sparfosic acid; Spicamycin D; Spiromastine; Splenopentin; Spongestatin 1; Squalamine; Stem cell inhibitor; Stem cell division inhibitor; Stipiamide; Stromelysin inhibitor; Sulfinodine; Hyperactive vasoactive intestinal peptide antagonist ;Saladista;Suramin;Swainsonine;Synthetic glycosaminoglycans;Talimustine;Tamoxifen methiodide;Tauromastine;Tazarotene;Tecogalan sodium;Tegafur;Terlapyrium;Telomerase inhibitors;Temoporfin;Temozolomide;Teniposide;Tetrachlorodecaoxide;Tetrazomine;Saliblastine;Thiocoraline;Thrombopoietin;Thrombopoietin mimetics;Thymalfadine;Thymopoietin receptor agonists;Thymotrinan;Thyroid-stimulating hormone;Tin ethyl etioproprine;Tirapazamine;Titanocene dichloride;Topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; tricibirine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitor; urokinase receptor antagonists; vapreotide; variolin B; vector systems, erythrocyte gene therapy; veraresol; veramine; acromega; verteporfin; vinorelbine; vinzartine; vitaxin; vorozole; zanoteron; zeniplatin; zilascorub; and zinostatin stimalamer.

[0427] Other anti-cancer agents that can be used in combination with Btk inhibitor compounds include alkylating agents, antimetabolites, natural products, or hormones, such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., brusfan), nitrosoureas (e.g., carmustine, lomustine, etc.), or triazenes (e.g., dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0421] Examples of alkylating agents that can be used in combination with the Btk inhibitor compound include, but are not limited to, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., bursufane), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (e.g., decarbazine). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0422] Examples of anti-cancer drugs that act by arresting cells in the G2-M phase by stabilizing microtubules and that may be utilized in combination with a Btk inhibitor compound include, but are not limited to, the following marketed and developmental drugs: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (also known as Altorhyrtin A and Altorhyrtin C), Spongistatins (Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, also known as Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also known as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067, and TI-138067), COBRA 1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute)Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocin (also known as NSC-698666), 3-lAABE (Cytoskeleton / Mt. Sinai School of Medicine, A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), eluterobin (such as desmethyleluterobin, desacetyleluterobin, isoeluterobin A, and Z-eluterobin), carybeoside, carybeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (AstaMedica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (SPA-110, also known as trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0423] If an individual suffers from or is at risk for an autoimmune, inflammatory, or allergic disease, Compound 1 may be used with one or more of the following therapeutic agents, in any combination: immunosuppressants (e.g., tacrolimus, cyclosporine, rapamicin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolic acid, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), nonsteroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2-arylpropionates), or the like. anthracycline, benzodiazepine, benzodiazepines ...

[0424] <Kit / manufactured product> Kits and articles of manufacture are also described herein for use in the therapeutic methods of use described herein. Such kits include carriers, packages, or containers, such as vials, tubes, and the like, that are partitioned to receive one or more containers, each container containing one of the individual components used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials, such as glass or plastic.

[0425] The articles of manufacture provided herein include packaging materials. Packaging materials used to package pharmaceutical products include, for example, those described in U.S. Patent No. 5,323,907. Pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, jars, and any packaging material appropriate for the selected formulation and intended mode of administration and treatment.

[0426] In some embodiments, the compounds or compositions described herein are provided in a package or dispenser device that may contain one or more unit dosage forms containing the active ingredient. The compounds or compositions described herein are packaged alone or with other compounds, ingredients, or additives. In some embodiments, the package contains one or more containers filled with one or more of the ingredients of the pharmaceutical composition. In some embodiments, the package comprises metal or plastic foil, such as a blister pack. In some embodiments, the package or dispenser device is accompanied by administration instructions, such as instructions for administering the compound or composition to treat a neoplastic disease. In some embodiments, the package or dispenser is accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or animal administration. In some embodiments, such notice is, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs or approved product inserts. In some embodiments, compositions comprising a compound described herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated disease.

[0427] For example, the container contains Compound 1, optionally in a composition or in combination with another agent as disclosed herein. Such kits include an identifying instruction, label, or instructions for use in the methods described herein.

[0428] The kit typically includes a label and / or instructions describing the contents and a package insert with instructions for use. A set of instructions is also typically included.

[0429] In one embodiment, a label is on or associated with a packaging container. In one embodiment, a label is attached to a container when letters, numbers, or other indicia forming the label are affixed, molded, or engraved into the container itself. A label is associated with a container when it is present in a receptacle or carrier that also holds the container, for example, as a package insert. In one embodiment, a label is used to indicate that the contents should be used for a particular therapeutic application. The label also indicates instructions for using the contents, such as in the methods described herein.

[0430] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device containing one or more unit dosage forms comprising a compound provided herein. The pack comprises, for example, metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser device is accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or animal administration. Such notice may be, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs or approved product inserts. In one embodiment, compositions comprising a compound described herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated disease. [Example]

[0431] The following ingredients, formulations, processes, and procedures for carrying out the methods disclosed herein correspond to those described above.

[0432] Example 1: Preparation of crystalline form of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 1) <Form A-Path 1:> Amorphous Compound 1 (ca. 15 mg) was weighed into a vial. 10 volumes (150 μL) of solvent [methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, methanol, nitromethane, 10% aqueous acetone, or 10% aqueous isopropyl alcohol] were added to the vial. The vial was sealed and placed on a shaker at 50°C for 1 hour. If a slurry was obtained, 30 volumes (600 μL total) of solvent were added, and the slurry was then returned to 50°C for an additional hour. If the sample remained as a slurry at this point, no further solvent was added. The solution / slurry was stirred at 50°C for 1 hour, then cooled to 0°C at 0.1°C / min and held at 0°C overnight. When a slurry was obtained, the solids were filtered under vacuum to give Compound 1, Form A; due to slow evaporation through a pinhole, the solution was allowed to return to ambient temperature to give Compound 1, Form A.

[0433] <Form A-Path 2:> Amorphous Compound 1 (20 mg) was added to a vial, followed by the addition of a solvent (heptane (10 vol), dioxane (1 vol), toluene (10 vol), MTBE (10 vol), DIPE (10 vol), anisole (1 vol), ethyl acetate (10 vol), isopropyl acetate (10 vol), tetrahydrofuran (1 vol), DCM (1 vol), MIBK (10 vol), MEK (10 vol), acetone (10 vol), methanol (10 vol), ethanol (10 vol), acetonitrile (10 vol), nitromethane (1 vol), water (10 vol), or 10% aqueous isopropyl alcohol (1 vol). The sealed vial was placed in a maturation chamber (cycled between 50 °C and ambient temperature for 4 hours each) for 5 days before filtering the solid under vacuum to obtain Compound 1, Form A.

[0434] In some embodiments, amorphous Compound 1 was prepared by dissolving Compound 1, Form A (ca. 500 mg) in 10 ml of dichloromethane (DCM). The solvent was removed by rotary evaporation, occurring rapidly enough to prevent crystallization, to yield amorphous Compound 1.

[0435] <Form A-Path 3:> In a clean round-bottom flask, 12.0 grams of Compound 1 was dissolved in 120 ml of methanol by heating to 45°C with magnetic stirring. To the warm solution of dissolved Compound 1, 72 ml of water was added over 45 minutes, maintaining the internal temperature at 45°C. The solution slowly became a slurry, which was stirred at elevated temperature for 3 hours. A sample of the slurry was extracted, filtered, and dried. The slurry was cooled to room temperature and stirred for at least 16 hours. Another sample of the slurry was extracted, filtered, and dried. The solid was filtered, washed with 50 ml of a 3:2 mixture of methanol:water, and dried on the filter for 40 hours. 9.6 grams of Form A were obtained (melting point: first sample -152°C, second sample -154°C, main lot -154°C).

[0436] Form A was also obtained in a similar manner using aqueous acetone, ethanol, and n-propanol.

[0437] <Form B-Path 1:> Compound 1, Form A (ca. 100 mg) was weighed into a tube and dissolved in methanol (2 ml). The solution was heated to 50°C to ensure complete dissolution and then cooled to 5°C. Water was added to the solution at 5°C (200 μL until the sample became cloudy, for a total of 1000 μL). Seeds of Compound 1, Form C were added immediately after cloudiness occurred. The slurry was stirred for 1 day at 5°C. An aliquot was removed by pipette for analysis by XRPD, and the majority of the sample was retained. XRPD analysis highlighted the low crystallinity of the material, so the sample was held at 5°C for an additional 3 days. After this time, reanalysis of an aliquot of the sample showed that the material had converted to Compound 1, Form B. The sample was isolated by filtration under vacuum to obtain Compound 1, Form B.

[0438] <Form B-Path 2:> Compound 1, Form A (ca. 500 mg) was weighed into a tube and dissolved in methanol (4 ml) at 50° C. The solution was cooled to 25° C. and left to soak. Water was added until the solution became cloudy (at which point 500 μl of water was added, for a total of 2 ml). The slurry was stirred for 10 minutes. An aliquot was removed with a pipette and the material was evaluated by XRPD, while the sample was stirred for 1 hour at 25° C.; however, the material had very low crystallinity. After 1 hour of stirring at 25° C., the sample was placed at 5° C. for 3 days. After this time, another aliquot was removed with a pipette for XRPD analysis. The remainder of the slurry was filtered under vacuum and dried under vacuum overnight at 25° C. to obtain Compound 1, Form B.

[0439] <Form C:> In a clean round-bottom flask, 2.0 grams of Compound 1 was suspended in 25 ml of methanol and heated to 50°C. The warm solution of dissolved Compound 1 was filtered into a clean round-bottom flask. The clear solution was cooled to room temperature with magnetic stirring. The solution slowly became a slurry, which was stirred for 14 hours. The solid was filtered, washed with 5 mL of methanol, dried on the filter for 20 hours, and then dried in a vacuum oven at 50°C for 8 hours. 1.4 grams of Form C were obtained (mp = ∼132°C).

[0440] <Form D:> A dry mixture (ca. 5 mg of each component) was prepared using two of Compound 1 Forms A, B, or C. A slurry made from amorphous Compound 1 in MIBK was filtered to obtain a saturated solution. Ten volumes (100 μl) of the saturated solution were added to the dry mixture to prepare a new slurry. The slurry was stored at 5° C. for 3 days before filtering under vacuum to obtain Compound 1, Form D.

[0441] <Form E:> Amorphous Compound 1 (20 mg) was added to the vial, followed by seeds of Compound 1, Form C (ca. 5 mg). Ten volumes (200 μl) of toluene were added to the vial to prepare a slurry. The vial was sealed and aged for 1 day (4-hour cycles between 50°C and ambient temperature). Aliquots were removed by pipette for analysis by XRPD, TGA, and DSC; the data were consistent with Compound 1, Form E. However, after standing overnight at ambient temperature and drying at 40°C in vacuo for 1 day, the compound was found to have converted to Compound 1, Form A.

[0442] <Form F:> In a clean 20 ml scintillation vial, 200 mg of Compound 1 and 50 mg of activated charcoal were suspended in 4 ml of methanol and heated to 50°C. The resulting mixture was stirred for 2.5 hours at 50°C. The warm solution of dissolved Compound 1 was filtered through a syringe filter into a new, clean 20 ml vial, and the charcoal was removed. The cleared solution was allowed to cool to room temperature. The solution was aged for 1 week when, in the absence of stirring, several crystals were observed to form. After an additional 6 weeks, the bottom of the vial was covered with large crystals. The crystals were kept in a supersaturated methanol solution for analysis.

[0443] Example 2: X-ray powder diffraction (XRPD) X-ray powder diffraction patterns were collected on a Bruker AXS C2 GADDS or a Bruker AXS D8 diffractometer.

[0444] <Bruker Ax C2 GADDS> X-ray powder diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Ka radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automated sample positioning, and a HiStar 2D area detector. The X-ray optics consisted of a single Göbel multilayer mirror coupled with a 0.3 mm pinhole collimator. Weekly performance checks were performed using a certified standard NIST 1976 Corundum (flat plate). The beam divergence (i.e., the effective diameter of the X-ray beam on the sample) was approximately 4 mm. A θ-θ continuous scanning mode was utilized with the sample (detector distance of 20 cm, giving an effective 2θ range of 3.2°-29.7°). Typically, samples were exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for WNT 4.1.16 and data was analyzed and processed using Diffrac Plus EVA v11.0.0.2 or v13.0.0.2.

[0445] Ambient conditions

[0446] Samples run under ambient conditions using a powder that could be accepted without polishing were prepared as flat specimens. Approximately 1-2 mg of sample was lightly pressed onto a glass slide to obtain a flat surface.

[0447] <Non-ambient conditions> Samples run under non-ambient conditions were mounted on a silicon wafer with thermal conductivity compound. The sample was then heated to the appropriate temperature at 10°C / min (unless otherwise stated) and then held isothermal for 1 min before data collection began.

[0448] <Bruker AXS D8 Advance> X-ray powder diffraction patterns were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA), a theta-2-theta goniometer, and a V4 aperture, receiving slits, a Ge monochromator, and a Lynxeye detector. The instrument was validated for performance using a certified Corundum standard (NIST 1976). The software used for data collection was Diffrac Plus XRD Commander v2.5.0, and data were analyzed and presented using Diffrac Plus EVA v11.0.0.2 or v13.0.0.2. Samples were run as flat specimens under ambient conditions using powder as received. Samples were gently packed into cavities and cut into clean, zero-background (510) silicon wafers. Samples were rotated in their own plane during analysis. Data collection details are as follows: Angle range: 2~42°2θ Step size: 0.05° 2θ Collection time: 0.5 seconds / process

[0449] <XRPD on Form A> The X-ray powder diffraction pattern for Form A is displayed in Figure 1. Characteristic peaks include 5.7±0.1° 2-theta, 13.6±0.1° 2-theta, 16.1±0.1° 2-theta, 18.9±0.1° 2-theta, 21.3±0.1° 2-theta, and 21.6±0.1° 2-theta.

[0450] Crystallinity was not affected after 1 week of storage at 40°C / 75% RH or after 1 week of storage at 25°C / 97% RH.

[0451] <XRPD on Form B> The X-ray powder diffraction pattern for Form B is displayed in Figure 5. Characteristic peaks include 5.2±0.1° 2-theta, 10.2±0.1° 2-theta, 16.5±0.1° 2-theta, 18.5±0.1° 2-theta, and 20.8±0.1° 2-theta.

[0452] Crystallinity was not affected after 1 week of storage at 40°C / 75% RH or after 1 week of storage at 25°C / 97% RH.

[0453] <XRPD on Form C> The X-ray powder diffraction for Form C is displayed in Figure 9. Characteristic peaks include 7.0±0.1° 2-theta, 14.0±0.1° 2-theta, 15.7±0.1° 2-theta, 18.2±0.1° 2-theta, 19.1±0.1° 2-theta, 19.5±0.1° 2-theta, 20.3±0.1° 2-theta, 22.1±0.1° 2-theta, and 22.9±0.1° 2-theta.

[0454] Crystallinity was not affected after 1 week of storage at 40°C / 75% RH or after 1 week of storage at 25°C / 97% RH.

[0455] XRPD on Form D The X-ray powder diffraction pattern for Form A is displayed in Figure 12. Characteristic peaks include 7.2±0.1° 2-theta, 8.0±0.1° 2-theta, 9.2±0.1° 2-theta, 14.5±0.1° 2-theta, 18.5±0.1° 2-theta, 19.5±0.1° 2-theta, 20.7±0.1° 2-theta, 21.0±0.1° 2-theta, 21.9±0.1° 2-theta, and 22.4±0.1° 2-theta.

[0456] XRPD on Form E The X-ray powder diffraction for Form E is displayed in Figure 14. Characteristic peaks include 7.8±0.1° 2-theta, 8.8±0.1° 2-theta, 16.1±0.1° 2-theta, 18.1±0.1° 2-theta, 19.3±0.1° 2-theta, 19.5±0.1° 2-theta, 20.5±0.1° 2-theta, 21.6±0.1° 2-theta, and 25.2±0.1° 2-theta.

[0457] XRPD on Form F A simulated XRPD pattern was generated for Form F. XRPD simulated patterns were generated from the single crystal data obtained from Example 3 (cif file) using Mercury CSD v3.1 (C.F. Macrae et al. J. Appl. Cryst. (2006), 39-3, 453-457) (XRPD pattern settings: CuKα 1.54056; Start / End 2 / 43 2θ°; PWHW(2θ°) 0.1). The data was then saved as raw files. The raw files were processed using Diffrac Plus EVA v.15,0,0,0 to generate a peak table of 2θ° / intensity (%).

[0458] The simulated X-ray powder diffraction pattern for Form F is displayed in Figure 16. Characteristic peaks include those at 6.2 ± 0.1° 2-theta, 10.1 ± 0.1° 2-theta, 17.6 ± 0.1° 2-theta, 18.6 ± 0.1° 2-theta, 20.0 ± 0.1° 2-theta, 20.4 ± 0.1° 2-theta, 20.7 ± 0.1° 2-theta, 22.4 ± 0.1° 2-theta, 23.0 ± 0.1° 2-theta, 23.2 ± 0.1° 2-theta, 24.4 ± 0.1° 2-theta, 25.1 ± 0.1° 2-theta, 27.6 ± 0.1° 2-theta, 29.3 ± 0.1° 2-theta, and 29.7 ± 0.1° 2-theta.

[0459] Example 3: Single crystal X-ray diffraction Single crystal X-ray diffraction data were collected and processed as follows:

[0460] [Table 5]

[0461] Form F was characterized at a temperature of approximately 100(2) K by unit cell parameters approximately equal to:

[0462] [Table 6]

[0463] Example 4: Fourier Transform Infrared (FTIR) Data were collected on a Perkin-Elmer Spectrum One fitted with a universal Attenuated Total Reflectance (ATR) sampling accessory. Data were collected and analyzed using Spectrum v5.0.1 software.

[0464] The infrared spectrum of Form A is displayed in Figure 2. The characteristic peaks observed in the infrared spectrum of Form A are 1584 cm -1 , 1240cm -1 , 1147cm -1 , 1134cm -1 , 1099cm -1 , 1067cm -1 , 985cm -1 , and 953 cm -1 Contains peaks at

[0465] The infrared spectrum of Form B is displayed in Figure 6. The characteristic peaks observed in the infrared spectrum of Form B are 1586 cm -1 , 1573cm -1 , 1562cm -1 , 1229cm -1 , 1166cm -1 , 1141cm -1 , 1103cm -1 , 1056cm -1 , 1033cm -1 , and 982 cm -1 Contains peaks at

[0466] Example 5: Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Heat capacity calibration was performed using sapphire, and energy and temperature calibrations were performed using certified indium. Typically, 0.5-3 mg samples in pinhole aluminum pans were heated from 25°C to 300°C at 10°C / min. A dry nitrogen purge at 50 ml / min was maintained over the sample unless otherwise noted. Modulated temperature DSC was performed using an underlying heating rate of 2°C / min and temperature modulation parameters of ±0.318 60°C (amplitude) every 60 seconds (duration). The instrument control software was Q Series v2.8.0.392 and Thermal Advantage v4.8.3Q, and data were analyzed using Universal Analysis v4.4A.

[0467] TGA data were collected on a TA Instruments Q500 TGA equipped with a 16-position autosampler. The instrument was temperature calibrated using certified alumel and nickel. Typically, 3-10 mg of each sample was loaded onto a pre-tarred aluminum DSC and heated at 10°C / min from ambient to 350°C. A nitrogen purge at 60 ml / min was maintained over the sample unless otherwise noted. The instrument control software was Q Series v2.8.0.392 and Thermal Advantage v4.8.3Q, and data were analyzed using Universal Analysis v4.4A.

[0468] <Form A> The DSC and TGA thermograms of Form A are displayed in Figures 3 and 4, respectively.

[0469] No weight loss was observed. The material is anhydrous.

[0470] In DSC (heating rate: 10°C / min or 20°C / min), an endotherm was observed with an onset at about 154°C and a peak at about 157°C. An exothermic peak was observed at 159°C.

[0471] <Form B> The DSC and TGA thermograms of Form B are displayed in Figures 7 and 8, respectively.

[0472] No weight loss was observed. The material is anhydrous.

[0473] In DSC (heating rate: 10°C / min or 20°C / min), an endotherm was observed with an onset at about 99-106°C and a peak at about 115-118°C.

[0474] <Form C> The DSC and TGA thermograms of Form C are displayed in Figures 10 and 11, respectively.

[0475] No weight loss was observed. The material is anhydrous.

[0476] In DSC (heating rate: 10°C / min or 20°C / min), an endotherm was observed with an onset at about 134-135°C and a peak at about 137-139°C.

[0477] <Form D> The TGA thermogram of Form D is displayed in FIG.

[0478] A total weight loss of 16.6-17.8%, equivalent to about 1 mole of MIBK, was observed by TGA in one or two steps.

[0479] <Form E> The DSC and TGA thermograms of Form E are displayed in FIG.

[0480] A weight loss of 16.5% w / w was observed in TGA associated with two endothermic events in DSC recorded at 85°C (onset) and 151°C (onset), which may correspond to desolvation phenomena.

[0481] Example 6: Gravimetric Vapor Sorption (GVS) Sorption isotherms were obtained using an SMS DVS Intrinsic Moisture Sorption Analyzer and controlled by the DVS Intrinsic Control Software v1.0.0.30. Sample temperature was maintained at 25°C by the instrument control. Humidity was controlled by mixing dry and humid nitrogen streams, with a total flow rate of 200 ml / min. Relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0-100% RH) located near the sample. Sample weight change (mass relaxation) as a function of % RH was constantly monitored with a microbalance (accuracy ±0.005 mg). Typically, 5-20 mg of sample was placed in a tarred mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% RH and 25°C (typical room conditions). Moisture sorption isotherms were run (two scans giving one full cycle) as outlined below. Standard isotherms were run at 25°C over a 0-90% RH range at 10% RH intervals. Data analysis was attempted in Microsoft Excel using DVS Analysis Suite v6.0.0.7. Samples were collected after completion of the isotherm and reanalyzed by XRPD.

[0482] [Table 7]

[0483] <Form A> The mass change was <0.3% w / w between 0-90% RH. The material is not hygroscopic. No significant changes were observed in XRPD after GVS analysis.

[0484] <Form B> The mass change was 2.3% w / w between 0-90% RH. No hysteresis was observed. No significant changes were observed in XRPD after GVS analysis.

[0485] Example 7: Thermodynamic water solubility Aqueous solubility was determined by suspending sufficient compound in water to obtain a maximum final concentration of ≥ 10 mg / ml of the parent free form of the compound. The suspension was equilibrated at 25°C for 24 hours, after which the pH was measured. The suspension was then filtered through a glass fiber C filter. The filtrate was then diluted by an appropriate factor, e.g., 101. Quantitation was performed by HPLC on a standard solution of approximately 0.25 mg / ml in DMSO. Different volumes of the standard, diluted, and undiluted sample solutions were injected. Solubility was calculated using the peak area, determined by integration of the peak found at the same retention time as the major peak in the standard injection.

[0486] [Table 8]

[0487] Analyses were performed using ChemStation software vB.02.01-SR1 on an Agilent HP1100 in-line system equipped with a diode array detector.

[0488] The solubility of Form A in aqueous solutions at different pH values ​​is presented in Table 3.

[0489] [Table 9]

[0490] The thermodynamic aqueous solubility of Form B at a pH of 7.42 was determined to be 0.0096 mg / ml.

[0491] Example 8: Determination of chemical purity HPLC analyses were performed on an Agilent HP1100 / 1200 system equipped with a diode array detector using ChemStation software using the methods detailed below.

[0492] [Table 10]

[0493] In some embodiments, Form A is greater than 95% pure by HPLC analysis. In some embodiments, Form A is greater than 96% pure by HPLC analysis. In some embodiments, Form A is greater than 97% pure by HPLC analysis. In some embodiments, Form A is greater than 98% pure by HPLC analysis. In some embodiments, Form A is greater than 99% pure by HPLC analysis. In some embodiments, Form A is greater than 99.8% pure by HPLC analysis.

[0494] In some embodiments, Form B is greater than 95% pure by HPLC analysis. In some embodiments, Form B is greater than 96% pure by HPLC analysis. In some embodiments, Form B is greater than 97% pure by HPLC analysis. In some embodiments, Form B is greater than 98% pure by HPLC analysis. In some embodiments, Form B is greater than 99% pure by HPLC analysis. In some embodiments, Form B is greater than 97.8% pure by HPLC analysis. In some embodiments, Form B is greater than 99.8% pure by HPLC analysis.

[0495] In some embodiments, Form C is greater than 95% pure by HPLC analysis. In some embodiments, Form C is greater than 96% pure by HPLC analysis. In some embodiments, Form C is greater than 97% pure by HPLC analysis. In some embodiments, Form C is greater than 98% pure by HPLC analysis. In some embodiments, Form C is greater than 99% pure by HPLC analysis. In some embodiments, Form C is greater than 99.4% pure by HPLC analysis.

[0496] Example 9: Determination of chemical purity The chiral purity of compound 1 was determined by normal-phase HPLC using a Lux Cellulose-1 chiral column. The mobile phase consisted of 20% isopropyl alcohol and 80% hexane. The enantiomers of 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one were detected at 260 nm. In one embodiment, compound 1 was dissolved in a 7:3 mixture of hexane and IPA to obtain a concentration of approximately 0.2 mg / mL, and the sample was analyzed for chiral purity. The content of the R enantiomer was determined by peak area normalization of the enantiomeric peak and is expressed as weight percent. In some embodiments, samples of Compound 1 contain less than 5.0%, less than 4.0%, less than 3.0%, less than 2.0%, or less than 1.0% of the (S)-isomer. In some embodiments, samples of Compound 1 contain less than 1.0% of the (S)-isomer.

[0497] <Solid oral dosage form> In some embodiments, crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are formulated into a solid oral dosage form. In some embodiments, the crystallinity of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is maintained in the solid oral dosage form. In some embodiments, crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are formulated into tablets. In some embodiments, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are formulated into pills. In some embodiments, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are formulated into capsules. In some embodiments, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are placed in capsules with or without excipients. In any of these embodiments, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are Form A. In any of these embodiments, the crystals of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one are Form B.In any of these embodiments, the crystalline l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is Form C. In any of these embodiments, the crystalline l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is Form D. In any of these embodiments, the crystalline l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is Form E. In any of these embodiments, the crystalline 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is Form F. In any of these embodiments, the crystalline 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is a mixture of two or more crystalline forms selected from the group consisting of Form A, Form B, Form C, Form D, Form E, and Form F.

[0498] Example 10: Capsule formulation In one embodiment, a capsule formulation of Compound 1 for administration to humans is prepared with the following ingredients:

[0499] [Table 11]

[0500] In some embodiments, the manufacturing process includes the following steps: weighing out the indicated amounts of the components, mixing them together, and adding them to capsules of appropriate size and similar. In some embodiments, the capsules are stored at room temperature for an extended period of time until use.

[0501] Example 11: Immediate release tablets In some embodiments, tablets are prepared with the ingredients set forth in Table 10.

[0502] [Table 12]

[0503] Manufacturing processes are typically granulation (dry, wet, or melt) or direct compression.

[0504] Example 12: Safety and tolerance study of Compound 1 in chronic lymphocytic leukemia Objective: The objective of this study was to establish the safety and optimal dose of orally administered compound 1 (420 mg / day) in patients with B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma / diffuse differentiated lymphocytic lymphoma.

[0505] Primary endpoint: Safety and tolerability of Compound 1 (frequency, severity, and relevance of adverse events).

[0506] Secondary endpoints: Pharmacokinetic / pharmacodynamic assessment. Tumor response - overall response rate as defined by current guidelines for CLL and SLL (B-cell lymphoma), and duration of response.

[0507] Eligibility: 18 years of age or older; both genders are eligible.

[0508] Inclusion Criteria: 1. For the treatment-naive group only: Men and women ≥ 65 years of age with a confirmed diagnosis of CLL / SLL who require treatment per NCI or International Working Group guidelines 11-14. 2. For the relapsed / refractory group only: Men and women ≥ 18 years of age with a confirmed diagnosis of relapsed / refractory CLL / SLL who are unresponsive to treatment (i.e., have failed ≥ 2 prior treatments for CLL / SLL, and at least one regimen must have included a purine analog [e.g., fludarabine] for subjects with CLL). 3. Weight ≥ 40 kg. 4. ECOG performance status ≤ 2. 5. If sexually active and capable of bearing children, agree to use contraception during the study and for 30 days after the last dose of investigational drug. 6. Willing to participate in all required evaluations and procedures in this study protocol, including being able to swallow a capsule without difficulty. 7. Understands the purpose and risks of the research and is able to sign and date informed consent and authorization for use of protected health information (in accordance with national and local subject privacy regulations).

[0509] Exclusion Criteria: 1. Life-threatening illness, condition, or organ system dysfunction that, in the investigator's opinion, could compromise subject safety, interfere with absorption and metabolism of Compound 1 PO, or unduly jeopardize the results of the study. 2. Any immunotherapy, chemotherapy, radiation therapy, or experimental treatment within 4 weeks prior to the first dose of study drug (corticosteroids for disease-related symptoms are permitted but require a 1-week washout period before administration of study drug). 3. Central nervous system (CNS) involvement due to lymphoma. 4. Major surgery within 4 weeks prior to the first dose of study drug. 5. Creatinine >1.5 x histologic upper limit of normal (ULN); total bilirubin >1.5 x ULN (unless due to Gilbert's disease); and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 x ULN unless disease-related. 6. Concomitant use of medications known to cause QT prolongation or torsades de pointes. 7. Significant screening electrocardiogram (ECG) abnormalities, including left bundle branch block, 2nd degree AV block type II, 3rd degree block, bradycardia, and QTc > 470 msec. 8. Lactating or pregnant.

[0510] Example 13: Safety and efficacy of Compound 1 in subjects with relapsed / refractory mantle cell lymphoma (MCL) The primary objective of this study is to evaluate the efficacy of Compound 1 in relapsed / refractory subjects with mantle cell lymphoma (MCL). A secondary objective is to evaluate the safety of a fixed daily dosing regimen of Compound 1 (560 mg / day in capsule form) in this population.

[0511] Primary endpoint: To determine the number of participants who have a response to Compound 1.

[0512] Secondary endpoints: Measuring the number of participants with adverse events as an indicator of safety and tolerability. Measuring pharmacokinetics to help determine how the body responds to the study drug. Patients will be debriefed (to measure the number of participants who received debriefing in determining health-related quality of life).

[0513] Eligibility: 18 years of age or older; both genders are eligible.

[0514] Inclusion Criteria: Males and females ≥18 years of age. ECOG performance status ≤2. Pathologically confirmed MCL with documentation of either cyclin D1 or t(11;14) overexpression and measurable disease on cross-sectional imaging with the longest diameter ≥2 cm and measurable in two perpendicular dimensions. Documented failure to achieve at least a partial response (PR) or documented disease progression after the most recent treatment regimen. At least one, but fewer than five, previous treatment regimens for MCL (Note: Subjects who have received ≥2 cycles of prior treatment with bortezomib, either as a single agent or as part of a combination treatment regimen, will be considered exposed to bortezomib). Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing a capsule without difficulty. Understand the purpose and risks of the study and be able to sign and date informed consent and authorization for the use of protected health information (in accordance with national and local subject privacy regulations).

[0515] Key exclusion criteria: prior chemotherapy within 3 weeks, nitrosoureas within 6 weeks, therapeutic anticancer antibodies within 4 weeks, radiation or toxin immunoconjugates within 10 weeks, radiation therapy within 3 weeks, or major surgery within 2 weeks of the first dose of study drug. Any life-threatening illness, condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption and metabolism of Compound 1 capsules, or unduly jeopardize the results of the study. Clinically significant cardiac disease, such as uncontrolled or symptomatic arrhythmia, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach, small intestine, or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete intestinal obstruction. Any of the following laboratory abnormalities: 1. Absolute neutrophil count (ANC) < 750 cells / mm3 (0.75 x 109 / L) unless there is documentation of bone marrow involvement. 2. Platelet count < 50,000 cells / mm3 (50 x 109 / L) unrelated to fluid support unless there is documentation of bone marrow involvement. 3. Serum aspartate transaminase (AST / serum GOT) or alanine transaminase (ALT / serum GPT) > 3.0 x histologic upper limit of normal (ULN). 4. Creatinine > 2.0 x ULN.

[0516] Example 14: Phase 2 study of Compound 1 in combination with rituximab in patients with high-risk chronic lymphocytic leukemia and small lymphocytic lymphoma Objective: The goal of this clinical research study is to find out whether Compound 1, combined with rituximab, can help control chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The safety of this combination will also be studied.

[0517] Rituximab (375 mg / m ) given intravenously (IV) on days 1, 8, 15, and 22 2) was then followed once every 4 weeks on Day 1 only during Cycles 2-6. Compound 1 was administered orally daily at a dose of 420 mg (3 x 140 mg capsules) starting on Day 2 of Cycle 1 and continued daily.

[0518] Primary endpoint: Progression-Free Survival (PFS) [Time Frame: 3 months] - Progression-free survival defined as the time interval from treatment to progressive disease or death, whichever occurs first. All patients with complete response (CR), partial response (PR), or stable disease (SD) are counted as progression-free. Survival or time to progression function assessed using the Kaplan-Meier method.

[0519] Secondary endpoint: Toxicity [Timeframe: 3 months] - Toxicity reported by type, frequency, and severity. The grade of worst toxicity per patient was tabulated for selected adverse events and laboratory measurements. Toxicity (grade 3 or 4) was monitored based on a Bayesian model (beta-binomial) with the assumption of an a priori probability of toxicity after beta(1,1).

[0520] Eligibility: 18 years of age or older; both genders are eligible.

[0521] Inclusion Criteria: 1. Patients must have a diagnosis of high-risk CLL / SLL and must have previously been treated with up to three lines of prior therapy. High-risk CLL and high-risk SLL are defined by the presence of 17p deletion, 11q deletion, or TP53 mutation. Any CLL or SLL patient with a short remission duration of less than three years after prior first-line immunochemotherapy, such as an FCR regimen, also meets the criteria for high-risk CLL / SLL, regardless of the presence or absence of cytogenetic abnormalities. 2. CLL and SLL patients with 17p deletion or TP53 mutation are not required to have received any prior therapy, given the poor outcomes of CLL / SLL patients with standard first-line immunochemotherapy. Such patients are eligible if they are untreated or have received up to three lines of prior therapy. 3. Patients must have an indication for treatment according to the 2008 IWCLL criteria. 4. Patients must be >18 years of age at the time of signing the informed consent form. Understand and voluntarily sign informed consent. Able to comply with study procedures and follow-up examinations. ECOG / WHO performance status of 5.0-1. 6. Patients of childbearing potential must be willing to practice highly effective birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or partner sterilization) during the study and for 30 days after the last dose of investigational drug. Women of childbearing potential include any women who have experienced menarche and have not undergone successful sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopausal is defined as: amenorrhea > / = 12 consecutive months without another cause and documented serum follicle-stimulating hormone (FSH) level >35 mIU / mL; men of childbearing potential are any men who have not been surgically sterilized.7. Appropriate kidney and liver function, as indicated by any of the following: total bilirubin <= 1.5 x the upper limit of the tissue-specific normal value (ULN), except for patients with elevated bilirubin due to Gilbert's disease who are recognized to be involved; ALT <= 2.5 x ULN; and an estimated creatinine clearance (CrCl) > 30 mL / min, as calculated by the Cockcroft-Gault equation, unless there is an associated disease. 8. No prior malignancy within 3 years, except for currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast. 9. A urine pregnancy test (within 7 days of Day 1) is required for women who may be pregnant.

[0522] Exclusion Criteria: 1. Pregnant or breastfeeding women. 2. Treatment within 21 days prior to enrollment or participation in this study, including chemotherapy, immunochemotherapy, monoclonal antibody therapy, radiation therapy, high-dose corticosteroid treatment (greater than 60 mg prednisone daily or equivalent), or immunotherapy. 3. Investigational drug received within 30 days prior to the first dose of investigational drug, or previously taking Compound 1. If any investigational drug was received before this time point, drug-related toxicity must have resolved to Grade 1 or less before the first dose of investigational drug. 4. Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as showing ongoing signs / symptoms related to infection and without improvement despite appropriate antibiotics or other treatment). 5. Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune thrombocytopenia (ITP). 6. Patients with severe hematopoietic insufficiency, as defined by an absolute neutrophil count of less than 500 / micro-L and / or a platelet count of less than 30,000 / micro-L at the time of screening for this protocol. 7. Any other severe comorbidity or history of severe organ dysfunction or disease involving the heart, kidney, liver, or other organ systems that would place the patient at undue risk for treatment with Compound 1 and rituximab. 8. Significant cardiac disease, such as uncontrolled or symptomatic arrhythmia, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. 9. Significant screening ECG abnormalities, including left bundle branch block, second-degree AV block type II, third-degree block, bradycardia, and QTc > 470 msec. 10. Any severe medical condition, laboratory abnormality, or psychiatric illness that would place the subject at unacceptable risk if the subject were to participate in the study. 11. History of stroke or cerebral hemorrhage within 6 months. 12. Evidence of bleeding diathesis or coagulation disorder. 13. Major surgical procedure, open biopsy, or significant trauma within 28 days prior to Day 1, anticipating a major surgical procedure during the course of the study. 14. Minor surgical procedure, fine needle aspiration, or core biopsy within 7 days prior to Day 1. Bone marrow aspiration and / or biopsy is permitted. 15. Severe, non-healing wounds, ulcers, or fractures. 16. Treatment with Coumadin.Patients who have recently received Coumadin must stop Coumadin for at least 7 days before the start of the study. 17. Any chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, or fludarabine), immunotherapy (e.g., alemtuzumab or ofatumumab), bone marrow transplant, experimental therapy, or radiation therapy is prohibited during treatment on this study. 18. Use of medications known to prolong the QTc interval or that may be associated with torsades de pointes (see Appendix F) is prohibited within 7 days of starting study drug and during study drug treatment.

[0523] The examples and embodiments described herein are illustrative, and various modifications or changes suggested to those skilled in the art should be included within the present disclosure. As will be recognized by those skilled in the art, the specific components listed in the above examples can be replaced with other functionally equivalent components, such as excipients, binders, lubricants, fillers, etc.

Claims

1. 1. A pharmaceutical formulation for oral administration, comprising: (a) about 40 mg to about 200 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; (b) about 40 wt % to about 50 wt % diluent; (c) about 3 wt % to about 10 wt % of a disintegrant; (d) about 2 wt % to about 7 wt % of a surfactant; and (e) about 0.2 wt % to about 1.0 wt % of a lubricant 10. A pharmaceutical formulation comprising:

2. 2. The pharmaceutical formulation of claim 1, wherein the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microfine cellulose, and talc.

3. 3. The pharmaceutical formulation of claim 2, wherein the diluent is microcrystalline cellulose.

4. 2. The pharmaceutical formulation of claim 1, wherein the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked starches such as sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clays, or gums.

5. 5. The pharmaceutical formulation according to claim 4, wherein the disintegrant is croscarmellose sodium.

6. 2. The pharmaceutical formulation of claim 1, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, and copolymers of ethylene oxide and propylene oxide.

7. 7. The pharmaceutical formulation of claim 6, wherein the surfactant is sodium lauryl sulfate.

8. 2. The pharmaceutical formulation of claim 1, wherein the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and waxes.

9. 9. The pharmaceutical formulation of claim 8, wherein the lubricant is magnesium stearate.

10. (a) 140 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; (b) 45.9 wt% microcrystalline cellulose; (c) 7.0 wt% croscarmellose sodium; (d) 4.2 wt. % sodium lauryl sulfate; and (e) 0.5 wt% magnesium stearate 2. The pharmaceutical formulation according to claim 1, characterized in that it comprises:

11. 11. The pharmaceutical formulation according to any one of claims 1 to 10, wherein the dosage form is a hard gelatin capsule.

12. A package comprising one or more separate blister pockets, wherein each blister pocket contains: a) about 40 mg to about 200 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; b) about 40 wt % to about 50 wt % of a diluent; c) about 3 wt % to about 10 wt % of a disintegrant; d) about 2 wt % to about 7 wt % of a surfactant; and e) about 0.2 wt % to about 1.0 wt % of a lubricant a unit dosage form comprising: wherein each blister pocket comprises a metal or plastic foil. A package characterized by:

13. Each unit dosage form contains: a) 140 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; b) 45.9 wt% microcrystalline cellulose; c) 7.0 wt% croscarmellose sodium; d) 4.2 wt. % sodium lauryl sulfate; and e) 0.5 wt% magnesium stearate.

13. The package of claim 12, comprising:

14. 1. Crystalline form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, which has the following characteristics: (a) X-ray powder diffraction (XRPD) pattern, substantially the same as that shown in Figure 1; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.7±0.1° 2-theta, 13.6±0.1° 2-theta, 16.1±0.1° 2-theta, 18.9±0.1° 2-theta, 21.3±0.1° 2-theta, and 21.6±0.1° 2-theta; (c) substantially the same X-ray powder diffraction (XRPD) pattern after storage at 40°C and 75% RH for at least one week; (d) substantially the same X-ray powder diffraction (XRPD) pattern after storage at 25°C and 97% RH for at least one week; (e) Infrared (IR) spectrum, substantially similar to that shown in Figure 2; (f) Approximately 1584cm －１ , approx. 1240cm －１ , approx. 1147cm －１ , approx. 1134cm －１ , approximately 1099 cm －１ , and approximately 1067 cm －１ a weak peak in the infrared (IR) spectrum at (g) DSC thermogram substantially similar to that shown in Figure 3; (h) Thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 4; (i) a DSC thermogram with an endotherm with an onset at about 154°C and a peak at about 157°C, and an exotherm at about 159°C; (j) non-hygroscopic; (k) an observed aqueous solubility of about 0.013 mg / mL at about pH 8; or (n) combinations thereof A crystalline form having at least one of the following:

15. 15. The crystalline form of claim 14, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 1.

16. 15. The crystalline form of claim 14, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.7±0.1°2-theta, 13.6±0.1°2-theta, 16.1±0.1°2-theta, 18.9±0.1°2-theta, 21.3±0.1°2-theta, and 21.6±0.1°2-theta.

17. 15. The crystalline form of claim 14, wherein the crystalline form has substantially the same X-ray powder diffraction (XRPD) pattern after storage at 40°C and 75% RH for at least 1 week.

18. 15. The crystalline form of claim 14, wherein the crystalline form has substantially the same X-ray powder diffraction (XRPD) pattern after storage at 25°C and 97% RH for at least 1 week.

19. 15. The crystalline form of claim 14, wherein the crystalline form has an infrared (IR) spectrum substantially similar to that shown in Figure 2.

20. The crystalline form is approximately 1584 cm －１ , approx. 1240cm －１ , approx. 1147cm －１ , approx. 1134cm －１ , approximately 1099 cm －１ , and approximately 1067 cm －１ 15. The crystalline form of claim 14, having a weak peak in the infrared (IR) spectrum at

21. 15. The crystalline form of claim 14, wherein the crystalline form has a melting temperature of about 155-156°C.

22. 15. The crystalline form of claim 14, wherein the crystalline form has a DSC thermogram substantially similar to that shown in Figure 3.

23. 15. The crystalline form of claim 14, wherein the crystalline form has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 4.

24. 15. The crystalline form of claim 14, wherein the crystalline form has a DSC thermogram comprising an endotherm with an onset at about 154°C and a peak at about 157°C, and an exotherm at about 159°C.

25. 15. The crystalline form of claim 14, wherein the crystalline form is non-hygroscopic.

26. 15. The crystalline form of claim 14, wherein the crystalline form has an observed aqueous solubility of about 0.013 mg / mL at about pH 8.

27. 15. The crystalline form of claim 14, wherein the crystalline form is characterized as having properties (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), and (k).

28. 28. The crystalline form of any one of claims 14 to 27, wherein the crystalline form is obtained from ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole, acetone, heptane, a mixture of methanol / water, or acetone / heptane.

29. 29. The crystalline form of any one of claims 14 to 28, wherein the crystalline form is not solvated.

30. 30. The crystalline form of any one of claims 14 to 29, wherein the crystalline form is anhydrous.

31. 12. The pharmaceutical formulation according to any one of claims 1 to 11, wherein 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is in crystalline form A.

32. 1. A pharmaceutical formulation for oral administration, comprising: (a) 140 mg of crystalline form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; (b) 45.9 wt% microcrystalline cellulose; (c) 7.0 wt% croscarmellose sodium; (d) 4.2 wt. % sodium lauryl sulfate; and (e) 0.5 wt% magnesium stearate 10. A pharmaceutical formulation comprising:

33. The package according to claim 12 or 13, characterized in that the 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is in crystalline form A.

34. 36. A method for treating cancer in a mammal, comprising administering to the mammal a pharmaceutical formulation according to any one of claims 1 to 11, 31, or 32.

35. 35. The method of claim 34, wherein the cancer is a B-cell malignancy.

36. 35. The method of claim 34, wherein the cancer is a B-cell malignancy selected from chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma.

37. 35. The method of claim 34, wherein the cancer is lymphoma, leukemia, or a solid tumor.

38. 35. The method of claim 34, wherein the cancer is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Wandelstrom 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, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis, and if the subject is afflicted with cancer, an anti-cancer agent is administered to the subject in addition to one of the aforementioned compounds, and the anti-cancer agent is an inhibitor of mitogenic protein kinase signaling.

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