Crystalline forms of bruton tyrosine kinase inhibitor

<Related Application> This application claims the benefit of the US provisional patent application No. 61 / 655,381 filed on July 4, 2012, entitled "CRYSTAL LINE FORMS OF A BRUTON'S TYROSINE KINASE IN HIBITOR". The application is incorporated herein by reference in its entirety.

<Field of Invention> In the present specification, Bruton's tyrosine kinase (Btk) inhibitor, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d] pyrimidin-1-yl) piperidine-1-yl) prop-2-en-1-one (its crystal form, solvates, and pharmaceutically acceptable salts, as well as Btk inhibitors (Including pharmaceutical compositions containing), as well as how to use Btk inhibitors in the treatment of diseases or diseases that benefit from inhibition of Btk activity.

Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is an important signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Is. Btk plays an important role in the B cell signaling pathway that links cell surface B cell receptor (BCR) stimulation to downstream intracellular reactions.

Btk is an important regulator of B cell development, activation, signal transduction, and survival. In addition, Btk plays a role in many other hematopoietic cell signaling pathways (eg, TNF-α production mediated by Toll-like receptors (TLRs) and cytokine receptors in macrophages, IgE receptors in obese cells (eg, IgE receptors in obese cells). Fcepsilon RI) signaling, inhibition of Fas / APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation).

1-((R) -3- (4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine-1-yl) piperidine-1-yl) prop-2-en -1-one is also 1-{(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidine-1- Il} prop-2-en-one or 2-propen-1-one, 1-[(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] Pyrimidine-1-yl] -1-piperidinyl-known by its IUPAC name and given the USAN name, ibrutinib. The various names given for ibrutinib are used interchangeably herein.

Btk inhibitors, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine, are described herein. -1-yl) prop-2-en-1-one (including pharmaceutically acceptable solvates (including hydrates), polymorphic, and amorphous phases), and how to use them. However, it is described. Also described are pharmaceutically acceptable salts of Btk inhibitors (including pharmaceutically acceptable solvates (including hydrates), polymorphic, and amorphous phases) and their use. Will be done. 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 its pharmaceutically acceptable salt, is also used in the manufacture of drugs 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.

As described herein, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) A method for preparing the crystal form of prop-2-en-1-one is also described. In addition, pharmaceutical compositions containing crystalline forms and Btk inhibitors in the treatment of diseases or diseases, including diseases or diseases in which irreversible inhibition of Btk provides a therapeutic effect on the disease or mammal with the disease. The method to use is described.

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

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

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

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

In one embodiment, a solvate is described, wherein 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin. -1-yl) piperidine-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) piperidine-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) piperidine-1-yl) prop-2-en-1-one is solvated with methanol.

In a further embodiment, the solvate is anhydrous.

In another embodiment, the solvate is crystalline.

In yet another embodiment, the solvate is amorphous.

In one embodiment, the specification herein is 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,], which has at least one of the following properties: 4-d] Pyrimidine-1-yl) piperidin-1-yl) prop-2-en-1-one crystal form A is described: (a) X-ray powder, much the same as shown in Figure 1. Diffraction (XRPD) pattern; (b) 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-X-ray powder diffraction (XRPD) pattern with characteristic peaks at theta; (c) Approximately the same X-ray after storage at 40 ° C and 75% RH for at least 1 week Powder Diffraction (XRPD) Pattern; (d) Approximately the same X-ray Powder Diffraction (XRPD) Pattern after storage at 25 ° C and 97% RH for at least 1 week; (e) Similar to that shown in Figure 2. Infrared (IR) spectrum; (f) approx. 1584 cm^-1, About 1240 cm^-1, About 1147 cm^-1, About 1134cm^-1, About 1099 cm^-1, And about 1067 cm^-1Weak peaks in the infrared (IR) spectrum in; (g) DSC thermograms similar to those shown in Figure 3; (h) Thermogravimetric analysis (TGA) thermograms similar to those shown in Figure 4. (i) DSC thermogram with onset at about 154 ° C and heat absorption with a peak at about 157 ° C, and heat generation at about 159 ° C; (j) non-hygroscopic; (k) about Observed water solubility of about 0.013 mg / mL at pH 8; or (n) a combination thereof.

In some embodiments, crystal form A has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, crystal form A is 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-. It has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at theta and 21.6 ± 0.1 ° 2-theta. In some embodiments, Crystal Form A has approximately the same X-ray powder diffraction (XRPD) pattern after storage at 40 ° C and 75% RH for at least 1 week. In some embodiments, Crystal Form A has approximately the same X-ray powder diffraction (XRPD) pattern after storage at 25 ° C and 97% RH for at least 1 week. In some embodiments, crystal form A has an infrared (IR) spectrum similar to that shown in FIG. In some embodiments, crystalline form A is approximately 1584 cm.^-1, About 1240 cm^-1, About 1147 cm^-1, About 1134cm^-1, About 1099 cm^-1, And about 1067 cm^-1Has a weak peak in the infrared (IR) spectrum at. In some embodiments, crystal form A has a melting temperature of about 155-156 ° C. In some embodiments, crystalline form A has a DSC thermogram that closely resembles that shown in FIG. In some embodiments, crystal form A has a thermogravimetric analysis (TGA) thermogram that closely resembles that shown in FIG. In some embodiments, crystalline form A has a DSC thermogram with expression at about 154 ° C and endothermic with a peak at about 157 ° C, and exotherm at about 159 ° C. In some embodiments, crystalline form A is non-hygroscopic. In some embodiments, crystalline form A has an observed water solubility of about 0.013 mg / mL at about pH 8. In some embodiments, crystalline form A has the characterization (a), (b), (c), (d), (e), (f), (g), (h), (i), ( Characterized to have j), and (k). In some embodiments, the crystal form A is ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), It was obtained from 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, Crystal Form A is solvated. In some embodiments, crystal form A is anhydrous.

In one embodiment, the specification herein is 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,], which has at least one of the following properties: Crystal form B of 4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one is described: (a) X-ray powder, much the same as that shown in Figure 5. Diffraction (XRPD) pattern; (b) In 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 X-ray powder diffraction (XRPD) pattern with characteristic peaks; (c) Approximately the same X-ray powder diffraction (XRPD) pattern after storage at 40 ° C and 75% RH for at least 1 week; ( d) Approximately the same X-ray powder diffraction (XRPD) pattern after storage at 25 ° C and 97% RH for at least 1 week; (e) Infrared (IR) spectrum similar to that shown in Figure 6; (f) Approximately 1586 cm^-1, About 1573 cm^-1, About 1562 cm^-1, About 1229 cm^-1, About 1141 cm^-1, About 1103 cm^-1, About 1056 cm^-1, And about 1033 cm^-1Weak peaks in the infrared (IR) spectrum at; (g) DSC thermograms similar to those shown in Figure 7; (h) Thermogravimetric analysis (TGA) thermograms similar to those shown in Figure 8. (i) DSC thermogram with expression at about 99-106 ° C and heat absorption with a peak at about 115-118 ° C; (j) observed at about 0.0096 mg / mL at about pH 7.42 Water solubility; or (k) a combination thereof.

In some embodiments, crystal form B has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, crystal form B is 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. -Has an X-ray powder diffraction (XRPD) pattern with characteristic peaks in theta. In some embodiments, Crystal Form B has approximately the same X-ray powder diffraction (XRPD) pattern after storage at 40 ° C and 75% RH for at least 1 week. In some embodiments, Crystal Form B has approximately the same X-ray powder diffraction (XRPD) pattern after storage at 25 ° C and 97% RH for at least 1 week. In some embodiments, crystal form B has an infrared (IR) spectrum similar to that shown in FIG. In some embodiments, crystal form B is 1586 cm.^-1, About 1573 cm^-1, About 1562 cm^-1, About 1229 cm^-1, About 1141 cm^-1, About 1103 cm^-1, About 1056 cm^-1, And about 1033 cm^-1Has a weak peak in the infrared (IR) spectrum at. In some embodiments, crystalline form B has a DSC thermogram that closely resembles that shown in FIG. In some embodiments, crystal form B has a thermogravimetric analysis (TGA) thermogram that closely resembles that shown in FIG. In some embodiments, crystalline form B has a DSC thermogram with an endothermic expression at about 99-106 ° C and a peak at about 115-118 ° C. In some embodiments, crystalline form B has an observed water solubility of about 0.0096 mg / mL at a pH of about 7.42. In some embodiments, crystalline form B has properties (a), (b), (c), (d), (e), (f), (g), (h), (i), and Characterized to have (j). In some embodiments, crystal form B was obtained from a mixture of methanol and water. In some embodiments, crystal form B is solvated. In some embodiments, crystal form B is anhydrous.

In one embodiment, the specification herein is 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,], which has at least one of the following properties: Crystal form C of 4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one is described: (a) X-ray powder, much the same as shown in Figure 9. Diffraction (XRPD) pattern; (b) 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 X-ray powder diffraction (XRPD) pattern with characteristic peaks at ± 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 thermograms similar to those shown in Figure 10; (d) Thermogravimetric analysis (TGA) thermograms similar to those shown in Figure 11; (e) at approximately 99-106 ° C. DSC thermograms with onset and heat absorption with peaks at about 115-118 ° C; or (f) combinations thereof.

In some embodiments, crystal form C has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, the crystal form C is 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-. X-ray powder diffraction (XRPD) with characteristic peaks at 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. ) Has a pattern. In some embodiments, crystalline form C has a DSC thermogram that closely resembles that shown in FIG. In some embodiments, crystal form C has a thermogravimetric analysis (TGA) thermogram that closely resembles that shown in FIG. In some embodiments, crystalline form C has a DSC thermogram with an endothermic expression at about 134-135 ° C and a peak at about 137-139 ° C. In some embodiments, crystalline form C is characterized to have properties (a), (b), (c), (d), and (e). In some embodiments, crystal form C was obtained from a mixture of methanol and water. In some embodiments, Crystal Form C is solvated. In some embodiments, crystal form C is anhydrous.

In one embodiment, the specification herein is 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,], which has at least one of the following properties: Crystal form D of 4-d] pyrimidin-1-yl) piperidine-1-yl) prop-2-en-1-one is described: (a) X-ray powder, much the same as shown in Figure 12. Diffraction (XRPD) pattern; (b) 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 X with characteristic peaks at ± 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. Line powder diffraction (XRPD) patterns; (c) thermoweight analysis (TGA) thermograms similar to those shown in Figure 13; or (d) combinations thereof.

In some embodiments, crystal form D has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, the crystal form D is 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-. With characteristic peaks at 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. It also has an X-ray powder diffraction (XRPD) pattern. In some embodiments, Crystal Form D has a thermogravimetric analysis (TGA) thermogram that closely resembles that shown in FIG. In some embodiments, crystal form D is characterized as having properties (a), (b), and (c). In some embodiments, crystal form D was obtained from methyl isobutyl ketone (MIBK). In some embodiments, crystal form D is solvated. In some embodiments, crystalline form D is solvated with methyl isobutyl ketone (MIBK).

In one embodiment, the specification herein is 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,], which has at least one of the following properties: 4-d] Pyrimidine-1-yl) piperidin-1-yl) prop-2-en-1-one crystal form E is described: (a) X-ray powder, much the same as that shown in Figure 14. Diffraction (XRPD) pattern; (b) 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 X-ray powder diffraction (XRPD) pattern with characteristic peaks at ± 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 thermograms similar to those shown in Figure 15; (d) Thermogravimetric analysis (TGA) thermograms similar to those shown in Figure 15; or (e) combinations thereof.

In some embodiments, crystal form E has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, the crystal form E is 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-. X-ray powder diffraction (XRPD) with characteristic peaks at 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. ) Has a pattern. In some embodiments, crystalline form E has a DSC thermogram that closely resembles that shown in FIG. In some embodiments, crystal form E has a thermogravimetric analysis (TGA) thermogram that closely resembles that shown in FIG. In some embodiments, crystalline form E is characterized as having properties (a), (b), (c), and (d). In some embodiments, crystal form A was obtained from toluene. In some embodiments, crystal form E is solvated. In some embodiments, crystal form E is solvated with toluene.

In one embodiment, the specification herein is 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,], which has at least one of the following properties: 4-d] Pyrazin-1-yl) piperidin-1-yl) prop-2-en-1-one crystal form F is described: (a) X-ray powder, much the same as that shown in Figure 16. Diffraction (XRPD) pattern; (b) 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 X-ray powder diffraction (XRPD) pattern with characteristic peaks at ° 2-theta, 27.6 ± 0.1 ° 2-theta, and 29.3 ± 0.1 ° 2-theta; (c) at 100 (2) K Unit cell parameters approximately equal to the following:

<tables num="1"><img file="JP2020015744A_D0001.tif" /></tables>

Or (d) a combination thereof.

In some embodiments, crystal form F has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, the crystal form F is 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, It has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 25.1 ± 0.1 ° 2-theta, 27.6 ± 0.1 ° 2-theta, and 29.3 ± 0.1 ° 2-theta.

In some embodiments, crystal form F has unit cell parameters approximately equal to those at 100 (2) K:

<tables num="2"><img file="JP2020015744A_D0002.tif" /></tables>

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

In some embodiments, crystal form F is solvated. In some embodiments, crystalline form F is solvated with methanol.

In one embodiment, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -H-pyrazolo [3,4-d] pyrimidin-1-yl) is described herein. A pharmaceutically acceptable salt of piperidine-1-yl) prop-2-en-1-one is described, and 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.

In a further embodiment, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1) as described herein. -Il) A pharmaceutical composition comprising piperidine-1-yl prop-2-en-1-one and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents, and excipients. The article is provided. In some embodiments, the pharmaceutical composition comprises form A. In some embodiments, the pharmaceutical composition comprises form B. In some embodiments, the pharmaceutical composition. Includes 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. The article 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 in oral solid dosage form. is there.

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

In another aspect, the present specification provides a pharmaceutical formulation for oral administration, including:

(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) piperidine- 1-Il) prop-2-en-1-on;

(b) Approximately 40 wt% to approximately 50 wt% diluent;

(c) About 3 wt% to about 10 wt% disintegrant;

(d) Approximately 2 wt% to approximately 7 wt% surfactant; and

(e) Approximately 0.2 wt% to approximately 1.0 wt% lubricant.

In some embodiments, the diluents are lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, modified starch, microcrystalline cellulose, It is selected from the group consisting of fine cellulose and talc. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the disintegrant is natural starch, α-starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked. It is selected from the group consisting of crosslinked starches such as croscarmellose, sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactants are sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, polaxomers, bile salts, glycerin monostearate, ethylene oxide and propylene oxide. Selected from the group consisting of copolymers. 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. Will be done. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

(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) piperidine- 1-Il) prop-2-en-1-on;

(b) Approximately 40 wt% to approximately 50 wt% microcrystalline cellulose;

(c) Approximately 3 wt% to approximately 10 wt% croscarmellose sodium;

(d) Approximately 2 wt% to approximately 7 wt% sodium lauryl sulfate; and

(e) Approximately 0.2 wt% to approximately 1.0 wt% magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

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

(b) Approximately 40 wt% to approximately 50 wt% microcrystalline cellulose;

(c) Approximately 3 wt% to approximately 10 wt% croscarmellose sodium;

(d) Approximately 2 wt% to approximately 7 wt% sodium lauryl sulfate; and

(e) Approximately 0.2 wt% to approximately 1.0 wt% magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

(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-on;

(b) 45.9 wt% microcrystalline cellulose;

(c) 7.0 wt% sodium croscarmellose;

(d) 4.2 wt% sodium lauryl sulfate; and

(e) 0.5 wt% magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

(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-on;

(b) 151.4 mg of microcrystalline cellulose;

(c) 23.0 mg of croscarmellose sodium;

(d) 14.0 mg sodium lauryl sulfate; and

(e) 1.6 mg magnesium stearate.

In another aspect, the present specification provides a pharmaceutical formulation for oral administration, including:

(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) piperidine- 1-Il) prop-2-en-1-one crystal;

(b) Approximately 40 wt% to approximately 50 wt% diluent;

(c) About 3 wt% to about 10 wt% disintegrant;

(d) Approximately 2 wt% to approximately 7 wt% surfactant; and

(e) Approximately 0.2 wt% to approximately 1.0 wt% lubricant.

In some embodiments, the diluents are lactose, sucrose, dextrose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, fine cellulose, And selected from the group consisting of talc. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the disintegrant is natural starch, α-starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked. It is selected from the group consisting of cross-linked starches such as 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 surfactants are sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, polaxomers, bile salts, glycerin monostearate, ethylene oxide and propylene oxide. Selected from the group consisting of copolymers. 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. Will be done. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

(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) piperidine- 1-Il) prop-2-en-1-one crystal;

(b) Approximately 40 wt% to approximately 50 wt% microcrystalline cellulose;

(c) Approximately 3 wt% to approximately 10 wt% croscarmellose sodium;

(d) Approximately 2 wt% to approximately 7 wt% sodium lauryl sulfate; and

(e) Approximately 0.2 wt% to approximately 1.0 wt% magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

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

(b) Approximately 40 wt% to approximately 50 wt% microcrystalline cellulose;

(c) Approximately 3 wt% to approximately 10 wt% croscarmellose sodium;

(d) Approximately 2 wt% to approximately 7 wt% sodium lauryl sulfate; and

(e) Approximately 0.2 wt% to approximately 1.0 wt% magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

(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 crystal;

(b) 45.9 wt% microcrystalline cellulose;

(c) 7.0 wt% sodium croscarmellose;

(d) 4.2 wt% sodium lauryl sulfate; and

(e) 0.5 wt% magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

(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 crystal;

(b) 151.4 mg of microcrystalline cellulose;

(c) 23.0 mg of croscarmellose sodium;

(d) 14.0 mg sodium lauryl sulfate; and

(e) 1.6 mg magnesium stearate.

In some embodiments of the pharmaceutical formulations described above, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin- The crystal of 1-yl) piperidine-1-yl) prop-2-en-1-one is in crystal form A. In some embodiments of the pharmaceutical formulations described above, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin- The crystal of 1-yl) piperidine-1-yl) prop-2-en-1-one is in crystal form B. In some embodiments of the embodiments of the pharmaceutical formulations described above, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin- The crystal of 1-yl) piperidine-1-yl) prop-2-en-1-one is in crystal form C. In some embodiments of the embodiments of the pharmaceutical formulations described above, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin- The crystal of 1-yl) piperidine-1-yl) prop-2-en-1-one is in crystal form D. In some embodiments of the embodiments of the pharmaceutical formulations described above, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin- The crystal of 1-yl) piperidine-1-yl) prop-2-en-1-one is in crystal form E. In some embodiments of the pharmaceutical formulations described above, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin- The crystal of 1-yl) piperidine-1-yl) prop-2-en-1-one is in crystal form F. In some embodiments of the pharmaceutical formulations described above, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d] Pyrimidine-1-yl) piperidine-1-yl) prop-2-en-1-one crystals consist of morphology A, morphology B, morphology C, morphology D, morphology E, and morphology F. A mixture of two or more crystalline forms selected from. In another embodiment of the above-mentioned embodiment of the pharmaceutical formulation, the present specification provides a pharmaceutical formulation in which the dosage form is a hard gelatin capsule.

In another aspect, the present specification provides a pharmaceutical formulation for oral administration, including:

(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) piperidine- Crystal form of 1-yl) prop-2-en-1-one A;

(b) Approximately 40 wt% to approximately 50 wt% diluent;

(c) About 3 wt% to about 10 wt% disintegrant;

(d) Approximately 2 wt% to approximately 7 wt% surfactant; and

(e) Approximately 0.2 wt% to approximately 1.0 wt% lubricant.

In some embodiments, the diluents are lactose, sucrose, dextrose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, fine cellulose, And selected from the group consisting of talc. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the disintegrant is natural starch, α-starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose. , Cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactant consists of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salt, glycerin monostearate, a copolymer of ethylene oxide and propylene oxide. Selected from the group. 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. Will be done. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

(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) piperidine- Crystal form of 1-yl) prop-2-en-1-one A;

(b) Approximately 40 wt% to approximately 50 wt% microcrystalline cellulose;

(c) Approximately 3 wt% to approximately 10 wt% croscarmellose sodium;

(d) Approximately 2 wt% to approximately 7 wt% sodium lauryl sulfate; and

(e) Approximately 0.2 wt% to approximately 1.0 wt% magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

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

(b) Approximately 40 wt% to approximately 50 wt% microcrystalline cellulose;

(c) Approximately 3 wt% to approximately 10 wt% croscarmellose sodium;

(d) Approximately 2 wt% to approximately 7 wt% sodium lauryl sulfate; and

(e) Approximately 0.2 wt% to approximately 1.0 wt% magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

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

(b) 45.9 wt% microcrystalline cellulose;

(c) 7.0 wt% sodium croscarmellose;

(d) 4.2 wt% sodium lauryl sulfate; and

(e) 0.5 wt% magnesium stearate.

In some embodiments, the present specification provides pharmaceutical formulations for oral administration, including:

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

(b) 151.4 mg of microcrystalline cellulose;

(c) 23.0 mg of croscarmellose sodium;

(d) 14.0 mg sodium lauryl sulfate; and

(e) 1.6 mg magnesium stearate.

In another embodiment, the present specification provides 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) Approximately 40 wt% to approximately 50 wt% diluent; c ) About 3 wt% to about 10 wt% disintegrant; d) About 2 wt% to about 7 wt% surfactant; and e) About 0.2 wt% to about 1.0 wt% lubricant; where the formulation is a blister pack The unit dosage form inside, said blister pack contains metal or plastic foil. In some embodiments, the pharmaceutical formulation is: a) 140 mg of 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin- 1-Il) piperidine-1-yl) prop-2-en-1-one; b) 45.9 wt% microcrystalline cellulose; c) 7.0 wt% sodium crocarmellose; d) 4.2 wt% lauryl sulfate Sodium; and e) about 0.5 Containing wt% magnesium stearate, where the formulation is a unit dosage form in a blister pack, said blister pack comprises a metal or plastic foil.

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

In another embodiment, the present specification provides 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 crystal form A; b) about 40 wt% to about 50 wt% Diluent; c) Approximately 3 wt% to approximately 10 wt% disintegrant; d) Approximately 2 wt% to approximately 7 wt% surfactant; and e) Approximately 0.2 wt% to approximately 1.0 wt% lubricant; Is in the unit dosage form in a blister pack, said blister pack containing 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) piperidine-1-yl) prop-2-en-1-one; b) 45.9 wt% microcrystalline cellulose; c) 7.0 wt% croscarmellose sodium; d) 4.2 It contains wt% sodium lauryl sulfate; and e) about 0.5 wt% magnesium stearate, where the formulation is in unit dosage form in a blister pack, said blister pack comprising a metal or plastic foil.

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

Description of a plurality of oral dosage forms such as tablets or capsules, packaging such as bottles containing oral dosage forms, and use for administering oral dosage forms according to the methods described herein in one embodiment. A kit containing the book is provided. Unit-dose packaging, such as blister packs, provides a useful method for packaging oral dosage forms of the formulations described herein, and in other embodiments, kits when combined with instructions for use. Including. In other embodiments, detailed product information is included along with instructions for use in the kit. Blister packs are particularly useful with solid oral dosage forms and, in further embodiments, for example biday administration. In one embodiment, the solid unit dosage form of the formulation described herein is one or more tablets or capsules on a daily basis so that the dosage of the formulation described herein is adequately administered. Included in a blister pack, along with instructions for administering. In another embodiment, the solid unit dosage form is included in the blister pack, along with instructions for administering one or more tablets or capsules every other day so that the daily dose is adequately administered. ..

In one embodiment, the specification provides a method of treating a patient by administration of Compound 1. In some embodiments, the specification herein is a method of treating a disease, disorder, or disease that benefits 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 is provided in a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable salt. Including the step of administering a new solvent to a mammal.

In another embodiment, the specification herein is to inhibit Bruton's tyrosine kinase (Btk) activity, or to treat a disease, disorder, or disease that benefits from inhibition of Bruton's tyrosine kinase (Btk) activity. The use of compound 1 is provided.

In some embodiments, crystalline compound 1 is administered to humans.

In some embodiments, crystalline compound 1 is orally administered.

In other embodiments, crystalline compound 1 is used in the formulation of drugs for the inhibition of tyrosine kinase activity. In some other embodiments, crystalline compound 1 is used in the formulation of drugs for inhibition of Bruton's tyrosine kinase (Btk) activity.

In one embodiment, the specification provides a method of treating mammalian cancer, comprising the step of administering to the mammal the pharmaceutical composition described herein comprising Compound 1. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple. B-cell malignancies selected from 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, preB-cell lymphocytic leukemia, lymphocytic lymphoma / Wandell. Strem-type macroglobulinemia, spleen marginal zone lymphoma, plasmacytoid myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal ( Chest gland) Large-cell B-cell lymphoma, intravascular large-cell B-cell lymphoma, primary exudate lymphoma, Berkit lymphoma / leukemia, or lymphoma-like granulomatosis. In some embodiments, if the subject is suffering from cancer, the 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 cell division-induced protein kinase signaling.

In one embodiment, a method of treating a mammalian inflammatory or autoimmune disease comprising administering to the mammal the pharmaceutical composition described herein comprising Compound 1. Provided. In some embodiments, the inflammatory disease is asthma, vulvitis, ulvitis, capillary bronchitis, bronchitis, bursitis, cervical inflammation, cholangitis, cholangitis, colitis, conjunctivitis, cystitis, Lacrimal adenitis, dermatomyositis, dermatomyositis, encephalitis, endometritis, endometritis, enteritis, total enteritis, epicondylitis, accessory testicles, myocarditis, synovitis, gastrointestinal inflammation, gastroenteritis, hepatitis, suppuration Sweat adenitis, laryngitis, mammary adenitis, meningitis, myelitis myocarditis, myitis, nephritis, ovitis, testicular inflammation, osteoitis, otitis, pancreatitis, parotid inflammation, peritonitis, peritonitis, Throatitis, plebitis, phlebitis, interstitial pneumonia, pneumonia, proctitis, prostatic inflammation, nephritis, rhinitis, cholangitis, venous sinusitis, stomatitis, articular synovitis, tendonitis, tonsillitis, vine membrane Flame, dermatomyositis, bursitis, or vulvitis. In some embodiments, the autoimmune disease is inflammatory bowel disease, arthritis, autoimmune disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile chronic rheumatoid arthritis, juvenile arthritis, diabetes, severe myasthenia, Hashimoto thyroiditis, Ord thyroiditis, Graves' disease, Schegren's syndrome, multiple sclerosis, Gillan Valley syndrome, acute diffuse encephalomyelitis, Azison's disease, eyeball clonus / myokronus ataxia, tonic spondylitis, antiphospholipid antibody Syndrome, poor regeneration anemia, autoimmune hepatitis, Celiac disease, Good Pasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, cirrhosis, primary biliary cirrhosis, Reiter syndrome, hyperan arteritis, temporal artery Flame, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, systemic alopecia, Bechet's disease, chronic fatigue, autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular tension , Dermatosis, or genital pain.

A manufacturing item is provided that includes a packaging material, a compound 1 in the packaging material, and a label indicating compound 1 used for inhibiting the activity of a tyrosine kinase such as Btk.

In a further aspect, the specification provides a method of treating a mammalian autoimmune disease, comprising the step of administering Compound 1 to the mammal.

In a further aspect, the specification provides a method of treating a mammalian heterologous immune disease or disease, comprising the step of administering Compound 1 to the mammal.

In a further aspect, the specification provides a method of treating a mammalian inflammatory disease, comprising the step of administering Compound 1 to the mammal.

In a further aspect, the specification provides a method of treating mammalian cancer, comprising the step of administering Compound 1 to the mammal.

In a further aspect, the present specification provides a method of treating a disorder of thromboembolism in a mammal, comprising the step of administering Compound 1 to the mammal. Disorders of thromboembolism are, but are not limited to, myocardial infarction, angina, restenosis after angioplasty, restenosis after angioplasty, restenosis after aortic coronary artery bypass grafting, restenosis after aortic coronary artery bypass grafting, stroke, Includes transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, or deep vein thrombosis.

In another embodiment, a regulatory method is provided that includes the step of irreversibly inhibiting the activity of Btk or other tyrosine kinases in mammals, where the other tyrosine kinases form a covalent bond with Compound 1. By having a cysteine residue (including Cys481 residue) that can be shared with Btk, the method comprises administering to the mammal at least one effective amount of Compound 1. Including. In another embodiment, a regulatory method is provided that comprises the step of irreversibly inhibiting the activity of Btk in a mammal, wherein the method administers an effective amount of Compound 1 to the mammal at least once. including. In another embodiment, a method for treating a Btk-dependent or Btk-mediated disease or disorder is provided, the method comprising administering to the mammal at least one effective amount of Compound 1.

In another embodiment, a method for treating inflammation is provided that comprises administering to the mammal at least once an effective amount of Compound 1.

In a further embodiment, a method of treating cancer is provided that comprises administering to the mammal at least one effective amount of Compound 1. Types of cancer include, but are not limited to, pancreatic cancer and other solid or hematological malignancies.

In another aspect, a method for treating a respiratory disease is provided that comprises administering to the mammal at least one effective amount of Compound 1. In a further embodiment of this embodiment, the respiratory disease is asthma. In a further embodiment of this embodiment, the respiratory disease is, but is 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, asthma that develops in early childhood, asthma that develops in adulthood, cough-type asthma, occupational asthma , Includes steroid refractory asthma and seasonal asthma.

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

In another aspect, a method for treating an inflammatory response in the skin is provided, comprising the step of administering to the mammal at least once an effective amount of Compound 1. Such skin inflammatory reactions include, for example, dermatitis, contact dermatitis, eczema, urticaria, alcohol, and scarring. In another embodiment, there is provided a method for reducing psoriatic lesions in skin, joints, or other tissues or organs, comprising the step of administering to the mammal at least once an effective amount of Compound 1.

In another embodiment, the use of Compound 1 in the manufacture of a drug for the treatment of an inflammatory disease or disease in an animal, where the activity of Btk or other tyrosine kinase is due to the pathology and / or symptoms of the disease or disease, provides. And here, other tyrosine kinases with Btk by having at least one cysteine residue (including Cys481 residue) capable of forming a covalent bond with the irreversible inhibitor described herein. Share homogeneity. In one embodiment of this embodiment, the tyrosine kinase protein is Btk. In another or further aspect of this aspect, the inflammatory disease or disease is a respiratory, cardiovascular or proliferative disease.

In any of the aforementioned embodiments, Compound 1 is (a) systemically administered to a mammal; (b) orally administered to a mammal; (c) intravenously administered to a mammal; (d) administered by inhalation. (E) Administered by nasal administration; or (f) Administered by infusion into mammals; (g) Administered topically (transdermally) to mammals; (h) Administered by instillation; (i) Further embodiments are provided that are administered rectally to a mammal.

In any of the aforementioned embodiments, further embodiments in which Compound 1 is administered (i) once, (ii) multiple times over a period of one day; (iii) frequently; or (iv) continuously. Further embodiments comprising a single dose of Compound 1 are provided.

In any of the aforementioned embodiments, (i) Compound 1 is administered in a single dose; (ii) Multiple doses are spaced every 6 hours and (iii) Compound 1 is administered every 8 hours to the mammal. Provided are additional embodiments comprising multiple doses of compound 1, comprising further embodiments administered to. In a further or alternative embodiment, the method comprises a drug holiday, where administration of Compound 1 is temporarily suspended, or the dose of Compound 1 is temporarily reduced; of the drug holiday. At the end, administration of compound 1 is resumed. The length of the drug holiday can vary from 2 days to 1 year.

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 (ie, by HPLC, more than 99% chiral purity). 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. A) Compound 1 with low chiral purity, or a pharmaceutically acceptable salt or solvate thereof; b) 1-((S) -3- (4-amino-3- (4)) with any optical purity. -Phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one, 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, Alternatively, it is replaced with a pharmaceutically acceptable salt or solvate thereof.

Amorphous compound 1 is used in any of the embodiments disclosed herein (including methods, uses, formulations, combination therapies, etc.). 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.

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 compound 1. Is replaced by the active metabolite of. In some embodiments, the active metabolite is in crystalline form. In some embodiments, the active metabolite is in the amorphous phase. In a further embodiment, the metabolites are separated. 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 compound 1. Is replaced by a prodrug of, or a deuterated analog of compound 1, or a pharmaceutically acceptable salt thereof.

Other objectives, features, and advantages of the methods and compositions described herein will become apparent from the detailed description below. However, although the detailed description and specific examples show a particular embodiment, various changes and modifications within the spirit and scope of the present disclosure will be apparent to those skilled in the art from this detailed description. Therefore, please understand that it is given only as an example purpose. The section titles used herein are for organizational purposes only and are not construed as limiting the subject matter described. All documents, including but not limited to patents, patent applications, treatises, books, manuals, and editorials, or any part of a document, is made clear herein by citation in its entirety for any purpose. Be incorporated.

&lt;Incorporation by Citation&gt; All publications and patent applications mentioned herein are incorporated herein by reference to the extent applicable and relevant.

<figref num="1">The X-ray powder diffraction (XRPD) pattern of Form A is shown.</figref><figref num="2">The infrared (IR) spectrum of Form A is shown.</figref><figref num="3">The DSC thermogram of form A is shown.</figref><figref num="4">The thermogravimetric analysis (TGA) thermogram of Form A is shown.</figref><figref num="5">The X-ray powder diffraction (XRPD) pattern of Form B is shown.</figref><figref num="6">The infrared (IR) spectrum of Form B is shown.</figref><figref num="7">The DSC thermogram of form B is shown.</figref><figref num="8">The thermogravimetric analysis (TGA) thermogram of Form B is shown.</figref><figref num="9">The X-ray powder diffraction (XRPD) pattern of Form C is shown.</figref><figref num="10">The DSC thermogram of form C is shown.</figref><figref num="11">The thermogravimetric analysis (TGA) thermogram of Form C is shown.</figref><figref num="12">The X-ray powder diffraction (XRPD) pattern of Form D is shown.</figref><figref num="13">The thermogravimetric analysis (TGA) thermogram of Form D is shown.</figref><figref num="14">The X-ray powder diffraction (XRPD) pattern of Form E is shown.</figref><figref num="15">The DSC thermogram and thermogravimetric analysis (TGA) thermogram of Form E are shown.</figref><figref num="16">The simulated X-ray powder diffraction (XRPD) pattern of Form F is shown.</figref>

The diverse role played by Btk signaling in various hematopoietic cell functions (eg, B cell receptor activation) is that small Btk inhibitors, such as compound 1, are responsible for many cells in hematopoetic lineage. Risk of various diseases (eg, autoimmune disease, heterologous immune disease or disease, inflammatory disease, cancer (eg, B cell proliferative disorder), and thromboembolism disorder) that are or are affected by It suggests that it helps to reduce sex or treat them. In addition, irreversible Btk inhibitor compounds such as Compound 1 share homology with Btk by having cysteine residues (including cysteine 481 residues) that can form covalent bonds with irreversible inhibitors. It can be used to inhibit a small subset of tyrosine kinases.

In some embodiments, compound 1 can be used in the treatment of mammalian autoimmune diseases, the autoimmune disease is not limited, but is rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile chronic rheumatoid arthritis, juvenile. Rheumatoid arthritis, ulcer, diabetes, severe myasthenia, Hashimoto thyroiditis, Ord thyroiditis, Graves' disease, Schegren's syndrome, multiple sclerosis, Gillan Valley syndrome, acute diffuse encephalomyelitis, Azison's disease, eyeball clonus myokronus Ataxia, tonic spondylitis, antiphospholipid antibody syndrome, regenerative anemia, autoimmune hepatitis, celiac disease, good pasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, cirrhosis, primary bile Liver cirrhosis, Reiter syndrome, hyperan arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, systemic alopecia, Bechet's disease, chronic fatigue, autoimmune disorders, endometriosis , Includes interstitial cystitis, neuromuscular tension, cirrhosis, and genital pain.

In some embodiments, Compound 1 can be used in the treatment of a heterologous immune disorder or disease in a mammal, the heterologous immune disorder or disease, including but not limited to implant-to-host disease, transplantation, blood transfusion, anaphylaxis, allergy. (For example, allergies to plant pollen, latex, drugs, food, insect poisons, animal hair, animal indulgence, chili ticks, or cockroach Calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic skin. Including flames.

In some embodiments, Compound 1 can be used in the treatment of inflammatory diseases in mammals, the inflammatory diseases are not limited to, asthma, inflammatory bowel disease, vulvitis, blebitis, bursitis, Bronchitis, bursitis, cervical inflammation, cholangitis, cholangitis, colitis, conjunctivitis, cystitis, lacrimal adenitis, dermatomyositis, dermatomyositis, encephalitis, endocarditis, endometriitis, enteritis, Total enteritis, epicondylitis, accessory testicles, myositis, synovitis, gastrointestinal inflammation, gastroenteritis, hepatitis, purulent sweat adenitis, laryngeal inflammation, mammary inflammation, meningitis, myelitis myositis, myositis, nephritis , Ovitis, testicular inflammation, osteoitis, otitis, pancreatitis, parotid adenitis, peritonitis, peritonitis, pharyngitis, plebitis, phlebitis, interstitial pneumonia, pneumonia, proctitis, prostatic inflammation, nephritis , Rhinitis, ear canalitis, phlebitis, stomatitis, bursitis arthritis, tendonitis, tonsillar inflammation, dermatomyositis, sheath inflammation, vasitis, and vulvitis.

In yet other embodiments, the methods described herein can be used to treat cancer, such as B-cell proliferative disorders, the cancer being, but not limited to, diffuse large B-cell lymphoma. Follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, pre-B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma / Wanderstrem type macroglobulinemia, spleen marginal zone lymphoma, plasmacytoid myeloma , Plasma cell tumor, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, medial (chest gland) large cell B cell lymphoma, intravascular large cell B cell lymphoma, Includes primary exudate lymphoma, Berkit lymphoma / leukemia, and lymphoma-like granulomatosis.

In a further embodiment, the methods described herein can be used to treat a disorder of thromboembolism, the disorder of thromboembolism is not limited, but myocardial infarction, angina (unstable). Includes angina), restenosis or restenosis after angiogenesis or aortic coronary bypass, stroke, temporary ischemia, peripheral arterial obstruction, pulmonary embolism, and deep venous thrombosis.

&lt;Blood Malignancies&gt; In a particular embodiment, a method of treating a blood malignant tumor of an individual in need is disclosed, the method of which is an amount of Compound 1 in an individual. Includes the step of administering.

In some embodiments, the hematological malignancies are non-Hodgkin's lymphoma (NHL). In some embodiments, the hematological malignancies are chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some embodiments, the hematological malignancies are follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrem macroglobulinemia, multiple myeloma. Tumor (MM), peripheral zone lymphoma, Burkitt lymphoma, non-Burkitt advanced B-cell lymphoma, or extranodal peripheral zone B-cell lymphoma. In some embodiments, the hematological malignancies are acute or chronic myelogenous (or spinal) leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, or B progenitor cell acute lymphocytic leukemia. In some embodiments, the hematological malignancies are chronic lymphocytic leukemia (CLL). In some embodiments, the hematological malignancies are mantle cell lymphomas (MCLs). In some embodiments, the hematological malignancies are diffuse large B-cell lymphomas (DLBCL). In some embodiments, the hematological malignancies are a subtype of ABC of diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancies are GCB subtypes of diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancies are Waldenström macroglobulinemia (WM). In some embodiments, the hematological malignancies are chronic lymphocytic leukemia myeloma (MM). In some embodiments, the hematological malignancies are Burkitt lymphomas. In some embodiments, the hematological malignancies are follicular lymphoma (FL). In some embodiments, the hematological malignancies are transformed follicular lymphomas. In some embodiments, the hematological malignancies are marginal zone lymphomas.

In some embodiments, the hematological malignancies are relapsed or refractory non-Hodgkin's lymphoma (NHL). In some embodiments, the hematological malignancies are relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma (MCL), relapsed or refractory follicle. Recurrent or refractory CLL, relapsed or refractory SLL, relapsed or refractory multiple myeloma, relapsed or refractory Waldenstrem macroglobulinemia, recurrent Or refractory multiple myeloma (MM), relapsed or refractory peripheral band lymphoma, relapsed or refractory Burkitt lymphoma, relapsed or refractory non-Burkitt advanced B-cell lymphoma, recurrent Or refractory extranodal marginal zone B-cell lymphoma. In some embodiments, the hematological malignancies are relapsed or refractory acute or chronic myelogenous (or myelogenous) leukemia, relapsed or refractory myelodysplastic syndrome, relapsed or refractory acute lymphoblastic. Sexual leukemia, or relapsed or refractory B progenitor cell acute lymphocytic leukemia. In some embodiments, the hematological malignancies are relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the hematological malignancies are relapsed or refractory mantle cell lymphoma (MCL). In some embodiments, the hematological malignancies are relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancies are a subtype of ABC of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancies are GCB subtypes of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancies are relapsed or refractory Waldenström macroglobulinemia (WM). In some embodiments, the hematological malignancies are relapsed or refractory chronic lymphocytic leukemia myeloma (MM). In some embodiments, the hematological malignancies are recurrent. Or refractory Burkitt lymphoma. In some embodiments, the hematological malignancies are relapsed or refractory follicular lymphoma (FL).

In some embodiments, the hematological malignancies are hematological malignancies that are classified as high risk. In some embodiments, the hematological malignancies are high-risk CLLs or high-risk SLLs.

B-cell lymphoproliferative disorder (BCLD) is a tumor of the blood, including non-Hodgkin's lymphoma, multiple myeloma, and leukemia, among others. BCLD can occur in either lymphoid tissue (as in the case of lymphoma) or bone marrow (as in the case of leukemia and myeloma), all of which are associated with uncontrolled growth of lymphocytes or white blood cells. There are many subtypes of BCLD (eg, chronic lymphocytic leukemia (CLL), and non-Hodgkin's lymphoma (NHL)). The disease course and treatment of BCLD depends on the subtype of BCLD; but even within each subtype, clinical symptoms, morphological appearance, and response to treatment are mixed.

Malignant lymphoma is a malignant transformation of cells that predominates in lymphoid tissue. The two groups of malignant lymphoma are Hodgkin lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphoma invade tissues of the reticular endothelial system. However, they differ in the new cells of origin, the site of the disease, the presence of systemic symptoms, and the response to treatment (Freedman et al., Non-Hodgkin's Lymphomas Chapter 134, Cancer Medicine, (American Cancer Society,). Approved publications of BC Decker Inc., Hamilton, Ontario, 2003)).

Non-Hodgkin's lymphoma

The specification discloses, in certain embodiments, a method of treating a non-Hodgkin's lymphoma in an individual in need, the method comprising administering to the individual an amount of Compound 1.

In addition, the specification discloses, in certain embodiments, a method of treating recurrent or refractory non-Hodgkin's lymphoma in an individual in need, which method is a therapeutically effective amount of Compound 1 in the individual. Includes the step of administering. In some embodiments, 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 recurrence. Sexual or refractory CLL.

Non-Hodgkin's lymphoma (NHL) is a diverse group of malignancies that are predominantly of B cell origin. NHL can progress in any organ associated with the lymphatic system, such as the spleen, lymph nodes, or tonsils, and can occur at any age. NHL is usually characterized by lymphadenopathy, fever, and weight loss. NHLs are classified as either B-cell or T-cell NHLs. The lymphoma associated with lymphoproliferative disorders after bone marrow or stem cell transplantation is usually B cell NHL. In the Working Formula Classification System, NHL was divided into low, moderate, or high categories according to their natural history (The Non-Hodgkin's Lymphoma Pathologic Classification Project, Cancer 49 (1982): See 2112-2135). Low-grade lymphomas are painless and have a median survival of 5-10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311: 1471-1475). Chemotherapy can induce remission of the majority of slow-chronic lymphomas, but treatment is rare and most patients eventually return to their original condition and require further treatment. Moderate and severe lymphomas are more active tumors, but they have greater opportunities for treatment with chemotherapy. However, a significant proportion of these patients return to their original condition and require further treatment.

An unrestricted list of B-cell NHL is Burkitt lymphoma (eg, endemic Burkitt lymphoma and diffuse Burkitt lymphoma), skin B-cell lymphoma, skin marginal zone lymphoma (MZL), diffuse large Diffuse Mixed Small and Large Cell Lymphoma (DLBCL), Diffuse Mixed Small and Large Cell Lympoma), diffuse small round cells, small lymphocytic lymphoma, extranodal marginal zone B cell lymphoma, follicular lymphoma, follicular small round cells (grade 1), follicular mixed small round cells and Taisho Round cells (grade 2), large follicular cells (grade 3), intravascular large-cell B-cell lymphoma, intravascular lymphoma, large immunoblastic lymphoma, large-cell lymphoma (LCL), lymphoblasts Sexual lymphoma, MALT lymphoma, mantle cell lymphoma (MCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) , Extranodal marginal zone B-cell lymphoma, mucosal-related lymphoma (MALT) lymphoma, large cell type B-cell lymphoma in the mediastinal sinus, peripheral zone B-cell lymphoma, spleen marginal zone B-cell lymphoma, early longitudinal Includes epithelial B-cell lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, Waldenstrem macroglobulinemia, and early central nervous system (CNS) lymphoma. Additional non-Hodgkin's lymphomas have been considered within the scope of the present invention and will be apparent to those skilled in the art.

DLBCL

The specification discloses, in certain embodiments, a method of treating DLBCL in a required individual, which method comprises administering to the individual an amount of Compound 1. Further herein, in certain embodiments, methods of treating recurrent or refractory DLBCL in an individual in need are disclosed, wherein the method administers a therapeutically effective amount of Compound 1 to the individual. Including the process of

As used herein, the term "diffuse large B-cell lymphoma (DLBCL)" refers to a germinal center B lymphocyte neoplasm with a dispersed growth pattern and a high-moderate proliferation index. .. DLBCL represents approximately 30% of all lymphomas and is present with a variety of morphological variants, including germinal center cells, immunoblastic, T cell / histiocyte-rich, undifferentiated and plasmablastic subtypes. Can be. Genetic testing showed the presence of different subtypes of DLBCL. These subtypes appear to have different appearances (prognosis) and responses to treatment. DLBCL can affect any age group, but most occur in the elderly (mean age is in the mid-60s).

The present specification discloses a method of treating a diffuse large B-cell lymphoma, an activated B-cell-like subtype (ABC-DLBCL) in a required individual in a particular embodiment. It comprises the step of administering to the individual an irreversible Btk inhibitor in an amount from 300 mg / day to 1000 mg / day. The ABC subtype (ABC-DLBCL) of diffuse large B-cell lymphoma is thought to arise from post germinal center B cells, which are blocked during plasma differentiation. The ABC subtype of DLBCL (ABC-DLBCL) accounts for approximately 30% of total DLBCL diagnoses. The most difficult to treat DLBCL molecular subtypes, and patients diagnosed with ABC-DLBCL, are typically considered to show a significant reduction in survival compared to individuals with other types of DLCBL. To. ABC-DLBCL is most commonly associated with chromosomal translocations that deregulate germinal center major regulator BCL6 and mutations that inactivate the PRDM1 gene, which encodes a transcriptional repressor required for plasma cell differentiation. To do.

A particularly relevant signaling pathway in the etiology of ABC-DLBCL is that it is mediated by the nuclear factor (NF) -κB transcription complex. The NF-κB family contains 5 members (p50, p52, p65, c-rel, and RelB), which form homodimers or heterodimers and undergo various proliferation, apoptosis, inflammatory and immune responses. It functions as a mediating transcription factor and has important implications for standard B cell progression and survival. NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB: that is, NF-κB is essentially active. Active NF-κB turns on the expression of genes that keep cells proliferating and protect them from diseases that kill them through apoptosis.

The dependence of ABC DLBCL on NF-κB depends on the signaling pathway upstream of the IkB kinase composed of CARD11, BCL10, and MALT1 (CBM complex). Interference by the CBM pathway abolishes NF-κB signaling in ABC DLBCL cells and induces apoptosis. The molecule underlying the constitutive activity of the NF-κB pathway is the subject of current research, but some somatic mutations into the genome of ABC DLBCL explicitly call this pathway. For example, somatic mutations in the coiled-coil domain of CARD11 in DLBCL allow this signaling backbone protein to spontaneously form nuclei from protein-protein interactions between MALT1 and BCL10, with IKK and NF-κB activity. Causes skeleton. The constitutive activity of the B cell receptor signaling pathway is ABCed by wild-type CARD11. It has been linked to activation of NF-κB in DLBCL, which is associated with mutations in the cytoplasmic tail of the B cell receptor subunits CD79A and CD79B. Tumorogenic activation mutations in the signaling adapter MYD88 show synergistic effects with B cell receptor signaling in activating NF-κB and sustaining ABC DLBCL cell survival. In addition, inactivating mutations in the negative regulator regulator (A20) of the NF-κB pathway occur almost exclusively in ABC DLBCL.

In fact, genetic alterations that affect the complex components of the NF-κB signaling pathway promote more than 50% of ABC-DLBCL in which these lesions promote constitutive NF-κB activation, thereby contributing to lymphoma growth. It has been identified in patients in recent years. These include mutations in lymphocyte-specific cytoplasmic scaffold proteins that form BCR signarosomes with CARD11 (in which case ~ 10%), MALT1 and BCL10, which are NF-κB activity from antigen receptors. The signal is relayed to the mediator downstream of the conversion. Even for larger fractions (~ 30%) carry genetic lesions of two alleles that inactivate the negative NF-κB regulator A20. In addition, high expression of the NF-κB target gene was 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 See -586).

DLBCL cells of the ABC subtype, such as OCI-Ly10, have chronic active BCR signaling and are highly sensitive to the Btk inhibitors described herein. The irreversible Btk inhibitors described herein potently and irreversibly inhibit the growth of OCI-Ly10 (EC).₅₀Continuous exposure = 10nM, EC₅₀ 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-G0 fraction, is observed in OCILy10. Sensitive and refractory cells express Btk at similar levels, and the active site of Btk is completely 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 that is dependently inhibited by the Btk inhibitors described herein. The activity of Btk inhibitors in cell lines discussed herein is also signal transduction properties (Btk, PLCγ, ERK, NF-κB, AKT), cytokine secretory properties, with and without BCR stimulation. And by comparing the mRNA expression characteristics, significant differences in these characteristics are observed that are characterized and lead to clinical biomarkers that identify the most sensitive patient population to Btk inhibitor treatment. U.S. Pat. No. 7,711,492, and Staudt et al., Nature, Refer to Vol. 463, Jan. 7, 2010, pp. 88-92, and the contents are incorporated by quoting the whole.

Follicular lymphoma

The specification discloses, in certain embodiments, a method of treating follicular lymphoma in an individual in need, the method comprising administering to the individual an amount of Compound 1. In addition, the specification discloses, in certain embodiments, a method of treating recurrent or refractory follicular lymphoma in an individual in need, which method is a therapeutically effective amount of Compound 1 in the individual. Includes the step of administering.

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 into nodules or follicles. The term "follicular" is used because cells tend to grow in a circular or nodular pattern in the lymph nodes. The average age of people with this lymphoma is about 60 years.

CLL / SLL

The specification discloses, in certain embodiments, a method of treating a CLL or SLL of an individual in need, the method comprising administering to the individual an amount of Compound 1. Further herein, in certain embodiments, methods of treating relapsed or refractory CLL or SLL in a required individual are disclosed, the method of which is a therapeutically effective amount of Compound 1 in the individual. Includes the step of administering.

Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL / SLL) are commonly considered as the same diseases with slightly different onset. Depending on where the cancer cells gather, it determines whether it is called CLL or SLL. When cancer cells are found primarily in the lymph nodes (the blue-eyed structure of the lymphatic system (a system of small blood vessels found primarily in the body)), they are called SLLs. SLL accounts for about 5% to 10% of all lymphomas. When most cancer cells are in the bloodstream and bone marrow, it is called CLL.

Both CLL and SLL are slow-growing diseases, but the much more common CLL tends to grow slowly. CLL and SLL are treated in the same way. Although they are usually not considered treatable with standard treatment, most patients live longer than 10 years, depending on the stage of the disease and the rate of growth. Sometimes over time, these slow-growing lymphomas can transform into more active forms of lymphoma.

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

CLL treatment is typically given if the patient's clinical symptoms or blood count indicate that the disease has progressed to a point where it can affect the patient's quality of life.

Small lymphocytic leukemia (SLL) is very similar to the CLL mentioned above and is also a B cell cancer. In SLL, abnormal lymphocytes mainly affect the lymph nodes. However, in CLL, abnormal cells mainly affect blood and bone marrow. The spleen can be affected in both conditions. SLL accounts for approximately 1 in 25 cases of all non-Hodgkin's lymphomas. It can occur at any time from adolescence to old age, but is rare under the age of fifty. SLL is considered to be slow chronic lymphoma. This means that the disease progresses very slowly and patients tend to live for years after diagnosis. However, most patients are diagnosed with advanced disease and SLL responds well to various chemotherapeutic agents, which are generally considered incurable. Some cancers tend to occur more frequently in either gender, but cases of SLL and death are equally divided between men and women. The average age at diagnosis is 60 years.

SLL is painless but permanently progressive. The usual pattern of the disease is a period of remission with a high response rate to radiation therapy and / or chemotherapy. This is followed by months or years with an unavoidable recurrence. Retreatment leads to a reaction again, but the disease returns to its original state. This means that while the short-term prognosis of SLL is fairly good, over time many patients develop 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 and effective treatment of the disease that does not interfere with the patient's quality of life and has minimal side effects. Exists. The present invention meets this long-standing need in the art.

Mantle cell lymphoma

The present specification discloses, in certain embodiments, a method of treating a mantle cell lymphoma of an individual in need, which method comprises administering to the individual an amount of Compound 1. In addition, the specification discloses, in certain embodiments, a method of treating recurrent or refractory mantle cell lymphoma in an individual in need, which method is a therapeutically effective amount of Compound 1 in the individual. Includes the step of administering.

As used herein, the term "mantle cell lymphoma" refers to CD5-positive antigen-naive pregerminal center B cells within the mantle that surrounds standard germinal center follicles. -cell), which refers to a subtype of B-cell lymphoma. MCL cells generally overexpress cyclin D1 due to the t (11:14) chromosomal translocation in DNA. More specifically, the dislocation is at t (11; 14) (q13; q32). Only about 5% of lymphomas are of this type. The cells are small to medium sized. People are most often affected. The average age of patients is in their early 60s. Lymph nodes are usually extensive when diagnosed and involve the lymph nodes, bone marrow, and very often the spleen. Mantle cell lymphoma is not a very fast-growing lymphoma, but it is difficult to treat.

Marginal zone B-cell lymphoma

The present specification discloses, in a particular embodiment, a method of treating a marginal zone B-cell lymphoma in an individual in need, which method comprises administering an amount of Compound 1 to the individual. Further herein, in certain embodiments, a method of treating recurrent or refractory marginal zone B-cell lymphoma in an individual in need is disclosed, which method provides the individual with a therapeutic effect on Compound 1. Includes the step of administering a specific amount.

As used herein, the term "marginal zone B-cell lymphoma" is a related B cell neoplasm containing lymphoid tissue in the marginal zone (the mottled area outside the mantle zone of the follicle). Refers to a group. Marginal zone lymphoma accounts for about 5% to 10% of lymphomas. The cells in these lymphomas appear small under a microscope. It includes three major types of marginal zone lymphoma: extranodal peripheral zone B-cell lymphoma, peripheral lymph node B-cell lymphoma, and peripheral spleen lymphoma.

MALT

The present specification discloses, in a particular embodiment, a method of treating MALT in a required individual, which method comprises administering to the individual an amount of Compound 1. Further herein, in certain embodiments, a method of treating a recurrent or refractory MALT in an individual in need is disclosed, wherein the method administers a therapeutically effective amount of Compound 1 to the individual. Including the process of

As used herein, the term "mucosa-associated lymphoid tissue (MALT) lymphoma" refers to extranodal development of marginal zone lymphoma. Most MALT lymphomas are of low grade, but a few are either initially manifested as medium grade non-Hodgkin's lymphoma (NHL) or develop from a low grade form. Most MALT lymphomas occur 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 about 60 years.

Peri-lymph node B-cell lymphoma

The present specification discloses, in a particular embodiment, a method of treating a peri-lymph node B-cell lymphoma in an individual in need, the method comprising administering to the individual an amount of Compound 1. Further herein, in certain embodiments, a method of treating a recurrent or refractory peri-lymph node B-cell lymphoma in an individual in need is disclosed, which method treats the individual with Compound 1. Including the step of administering an effective amount.

The term "peri-lymph node B-cell lymphoma" refers to painless B-cell lymphoma found mostly in the lymph nodes. The disease is rare and accounts for only 1% of all non-Hodgkin's lymphomas (NHL). It is most commonly diagnosed in older patients and is more susceptible to women than men. The disease is classified as marginal zone lymphoma because the mutation occurs in the marginal zone of B cells. Due to its limitation in the lymph nodes, the disease is also classified as nodular.

Peri-spleen zone B-cell lymphoma

The specification discloses, in certain embodiments, a method of treating a peri-spleen zone B-cell lymphoma of an individual in need, the method comprising administering to the individual an amount of Compound 1. Further, the present specification discloses a method for treating recurrent or refractory B-cell lymphoma of the peri-spleen zone in a required individual in a specific embodiment, and the method is used for treating Compound 1 in an individual. Includes the step of administering an effective amount.

The term "peri-spleen B-cell lymphoma" refers to a specific low-grade small B-cell lymphoma found in the World Health Organization classification. It is characterized by moderate lymphocyte hyperplasia of splenomegaly, with villous morphology, patterns within sinusoidal capillaries involving various organs, especially bone marrow, and a relative painless period. Tumor development with increased blast cell morphology and aggressive behavior is observed in a small number of patients. Molecular and cytogenetic studies have shown mixed results, probably due to the lack of standardized diagnostic criteria.

Burkitt lymphoma

The specification discloses, in certain embodiments, a method of treating Burkitt lymphoma in an individual in need, which method comprises administering to the individual an amount of Compound 1. Further herein, in certain embodiments, methods of treating recurrent or refractory Burkitt lymphoma in an individual in need are disclosed, the method of which is a therapeutically effective amount of Compound 1 in the individual. Includes the step of administering.

The term "Burkitt lymphoma" refers to a type of non-Hodgkin's lymphoma (NHL) that affects children in common. It is a very active type of B-cell lymphoma that frequently arises and contains from body parts other than the lymph nodes. Despite their fast-growing nature, Burkitt lymphoma is usually treatable with modern intensive care. There are two widespread types of Burkitt lymphoma (sporadic and endemic variants)

Endemic Burkitt lymphoma: The disease is much more associated with children than adults, and in 95% of cases is associated with Epstein-Barrvirus (EBV) infection. It originally occurs in Equatorial Africa, where about half of all childhood cancers are Burkitt lymphomas. It characteristically has a high probability associated with the mandible, i.e., a fairly differential feature that is rare in scattered Burkitt. It is also commonly associated with the abdomen.

Diffuse Burkitt Lymphoma: The types of Burkitt lymphoma that affect the rest of the world, including Europe and the Americas, are scattered types. Again, it is primarily a childhood illness. Direct evidence of Epstein-Barr virus (EBV) infection exists in one of five patients, but the link between EBVs is not as strong as in endemic variants. Beyond the involvement of lymph nodes, it is the abdomen that is significantly affected in more than 90% of children. Bone marrow involvement is more common than in scattered varieties.

Waldenström macroglobulinemia

The present specification discloses, in a particular embodiment, a method of treating Waldenström macroglobulinemia in an individual in need, which method comprises administering to the individual an amount of Compound 1. In addition, the specification discloses, in certain embodiments, a method of treating recurrent or refractory Waldenström macroglobulinemia in an individual in need, the method of treating the individual with Compound 1. Including the step of administering an effective amount.

The term "Waldenström macroglobulinemia," also known as lymphoplasmacytic lymphoma, is a cancer associated with 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 make antibodies called immunoglobulin M (IgM). IgM antibodies circulate in large quantities in the blood, thickening the liquid portion of the blood like a syrup. This can lead to reduced blood flow to many organs, which are neurological problems caused by leads, visual problems (due to poor circulation in the blood vessels behind the eye), and poor blood flow in the brain. Can cause (headache, dizziness, and confusion, etc.). Other symptoms may include a feeling of tiredness or weakness, and a tendency to bleed easily. Although the underlying etiology is not fully understood, many risk factors have been identified, including position 6p21.3 on chromosome 6. There is a 2-3-fold increased risk of advanced WM in people with a personal history of autoantibodies and autoimmune diseases with a particularly high risk associated with hepatitis, human immunodeficiency virus, and rickettsia disease To do.

Multiple myeloma

The specification discloses, in certain embodiments, a method of treating myeloma in an individual in need, the method comprising administering to the individual an amount of Compound 1. In addition, the specification discloses, in certain embodiments, a method of treating recurrent or refractory myeloma in an individual in need, which method provides the individual with a therapeutically effective amount of Compound 1. Includes the step of administration.

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

leukemia

The present specification discloses, in a particular embodiment, a method of treating leukemia in a required individual, which method comprises administering to the individual an amount of Compound 1. Further herein, in certain embodiments, a method of treating a recurrent or refractory leukemia in an individual in need is disclosed, wherein the method administers a therapeutically effective amount of Compound 1 to the individual. Including the process of

Leukemia is a blood cell, usually a white blood cell (white blood) A cancer of the blood or bone marrow, characterized by an abnormal increase in cells)). Leukemia is a broad term that covers a range of diseases. The first division lies between its acute and chronic forms: (i) Acute leukemia is characterized by a rapid increase in immature blood cells. This congestion 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 spread to other organs in the body. The acute morphology of leukemia is the most common form of leukemia in children; (ii) Chronic leukemia is relatively mature but still distinguished by an excessive accumulation of 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 many abnormal white blood cells in the blood. Chronic leukemia usually occurs in older people, but in theory it can occur in any age group. In addition, the disease is subdivided according to which blood cell type is affected. It is classified into lymphoblasts or lymphocytic leukocytes, and myeloid or osteosarcoma leukocytes: (i) Lymphoblasts or lymphocytic leukocytes, changes in cancer are immune system cells that reject infection. Occurs in a type of bone marrow cell, which normally progresses to form lymphocytes; (ii) myeloid or osteosarcoma leukemia, changes in cancer form red blood cells, some other type of white blood cell, and platelets It occurs in a type of bone marrow cell that normally progresses to.

Within these major categories, but not limited to, acute lymphoblastic leukemia (ALL), B precursor cell acute lymphoblastic leukemia (precursor B-ALL; also called precursor B lymphoblastic leukemia), There are various subcategories, including acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and hairy cell leukemia (HCL). Therefore, in a particular embodiment, the individual needs acute lymphoblastic leukemia (ALL), B precursor cell acute lymphoblastic leukemia (precursor B-ALL; precursor B lymphoblast). Methods for treating (also called spheroidal leukemia), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), or hairy cell leukemia (HCL) have been disclosed, in which the individual is given an amount of compound 1. Includes the step of administration. In some embodiments, the leukemia is a recurrent or refractory leukemia. In some embodiments, the leukemia is relapsed or refractory acute lymphoblastic leukemia (ALL), relapsed or refractory B precursor cell acute lymphoblastic leukemia (precursor B-ALL; precursor). B Lymphblastic leukemia), relapsed or refractory acute myelogenous leukemia (AML), relapsed or refractory chronic myelogenous leukemia (CML), or relapsed or refractory hairy cell leukemia (also called relapsed or refractory hairy cell leukemia) HCL).

Symptoms, diagnostic tests, and pre-examination tests for each of the aforementioned diseases are known. For example, Harrison's Principles of Internal Medicinec, "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, for example, the website managed by the National Cancer Institute).

Many animal models help establish a series of effective amounts of irreversible Btk inhibitor compounds, such as Compound 1, for the treatment of any of the aforementioned diseases.

The therapeutic effect of Compound 1 for any one of the aforementioned disorders can be optimized during the course of treatment. For example, the treated subject may be evaluated for diagnosis in order to correlate the reduction of symptoms or pathology to 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, phosphospecific immunocytoscientific staining of P-Y223 or PY551 positive cells is performed in the cell population because activated Btk is phosphorylated with tyrosine 223 (Y223) and tyrosine 551 (Y551). It can be used to detect or quantify the activation of Bkt (eg, by FACS analysis of stained cells vs. unstained cells). For example, Nisitani et al. (1999), Proc. Natl. Acad. See Sci, USA 96: 2221-2226. Therefore, the amount of Btk inhibitor compound administered to a subject can be increased or decreased as required to maintain optimal levels of Btk inhibition to treat the subject's disease state.

Compound 1 irreversibly inhibits Btk and is a Bruton's tyrosine kinase-dependent or Bruton's tyrosine kinase-mediated disease or disease, including but not limited to cancer, autoimmune and other inflammatory diseases. Can be used to treat mammals suffering from. Compound 1 has been shown to be effective for a wide variety of diseases and disorders described herein.

In some embodiments, Compound 1 is used in the manufacture of a drug for treating any of the aforementioned diseases (eg, autoimmune disease, inflammatory disease, allergic disorder, B cell proliferative disorder, or thromboembolic disorder). used.

&lt;Compound 1 and its pharmaceutically acceptable salts&gt; The Btk-inhibiting compounds described herein (ie, Compound 1) are at the amino acid sequence position of tyrosine kinase, which is homologous to the amino acid sequence position of cysteine 481 in Btk. It is selective for Btk and kinases that have cysteine residues. The Btk inhibitor compound can form a covalent bond of Btk with cysteine 481 (eg, via the Michael reaction).

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

<chemistry num="1"><img file="JP2020015744A_D0003.tif" /></chemistry>

A wide variety of pharmaceutically acceptable salts are formed from compound 1 and include:

Compound 1 with organic acids (including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc.) Acid addition salts formed by reaction, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartrate acid. , Citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

An acid addition salt formed by reacting Compound 1 with an inorganic acid (including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphite, etc.).

In connection with Compound 1, the term "pharmaceutically acceptable salt" refers to a salt of Compound 1, which does not cause significant irritating effects on the mammal to which it is administered, and the biological activity of the compound and It hardly suppresses the characteristics.

It should be understood that references to pharmaceutically acceptable salts include their solvated form (solvate). Solvents include either chemical or non-chemical quantities of the solvent and are pharmaceutically acceptable solvents (water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (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.) , Formed during the process of product formation or separation. In one embodiment, the solvate is formed using, but not limited to, Class 3 solvents. The solvent category is, for example, 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). Hydrate is formed when the solvent is water, or alcoholate is alcohol. In some embodiments, the solvate of Compound 1, or a pharmaceutically acceptable salt thereof, is conveniently prepared or formed during the process described herein. In one embodiment, the solvate of Compound 1 is anhydrous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is present in an unsolvated form. In the embodiment of, Compound 1 or a pharmaceutically acceptable salt thereof is present in an unsolvent form and is anhydrous.

In still other embodiments, compound 1 or a pharmaceutically acceptable salt thereof is prepared in a variety of forms, including, but not limited to, amorphous, crystalline, milled, 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.

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

&lt;Amorphous Compound 1&gt; In some embodiments, Compound 1 is amorphous and anhydrous. In some embodiments, compound 1 is amorphous. In some embodiments, the amorphous compound 1 has an X-ray powder diffraction (XRPD) pattern that shows a lack of crystallinity.

&lt;Compound 1, Form A&gt; In some embodiments, compound 1 is crystalline. In some embodiments, compound 1 is crystalline form A. Crystal form A of compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, much the same as that shown in Figure 1; (b) 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 X-ray powder diffraction (XRPD) pattern with characteristic peaks; (c) Approximately the same X-ray powder diffraction (XRPD) pattern after storage at 40 ° C and 75% RH for at least 1 week; (d) ) Approximately the same X-ray powder diffraction (XRPD) pattern after storage at 25 ° C and 97% RH for at least 1 week; (e) Infrared (IR) spectrum similar to that shown in Figure 2; ( f) Approximately 1584 cm^-1, About 1240 cm^-1, About 1147 cm^-1, About 1134cm^-1, About 1099 cm^-1, And about 1067 cm^-1Weak peaks in the infrared (IR) spectrum in; (g) DSC thermograms similar to those shown in Figure 3; (h) Thermogravimetric analysis (TGA) thermograms similar to those shown in Figure 4. (i) DSC thermogram with onset at about 154 ° C and heat absorption with a peak at about 157 ° C, and heat generation at about 159 ° C; (j) non-hygroscopic; (k) about Observed water solubility of about 0.013 mg / mL at pH 8; or (n) a combination thereof.

In some embodiments, Form A of Compound 1 is characterized by having at least two of the properties selected from (a)-(k). In some embodiments, Form A of Compound 1 is characterized by having at least three of the properties selected from (a)-(k). In some embodiments, Form A of Compound 1 is characterized by having at least four properties selected from (a)-(k). In some embodiments, Form A of Compound 1 is characterized by having at least five of the properties selected from (a)-(k). In some embodiments, Form A of Compound 1 is characterized by having at least six properties selected from (a)-(k). In some embodiments, Form A of Compound 1 is characterized by having at least seven of the properties selected from (a)-(k). In some embodiments, Form A of Compound 1 is characterized by having at least eight properties selected from (a)-(k). In some embodiments, Form A of Compound 1 is characterized by having at least nine properties selected from (a)-(k). In some embodiments, Form A of Compound 1 is characterized by having at least 10 of the properties selected from (a)-(k). In some embodiments, Form A of Compound 1 is characterized by having properties (a)-(k).

In some embodiments, embodiment A has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, embodiment A is 5.7 ± 0.1 ° 2-seater, 13.6 ± 0.1 ° 2-seater, 16.1 ± 0.1 ° 2-seater, 18.9 ± 0.1 ° 2-seater, 21.3 ± 0.1 ° 2-seater. , And 21.6 ± 0.1 ° 2-has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at theta. In some embodiments, Form A has approximately 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 approximately the same X-ray powder diffraction (XRPD) pattern after storage at 25 ° C and 97% RH for at least 1 week.

In some embodiments, embodiment A has an infrared (IR) spectrum similar to that shown in FIG. In some embodiments, Form A is about 1584 cm.^-1, About 1240 cm^-1, About 1147 cm^-1, About 1134cm^-1, About 1099 cm^-1, And about 1067 cm^-1Has a weak peak in the infrared (IR) spectrum at.

In some embodiments, embodiment A has a DSC thermogram that closely resembles that shown in FIG. In some embodiments, embodiment A has a thermogravimetric analysis (TGA) thermogram that closely resembles that shown in FIG. In some embodiments, Form A has a DSC thermogram with expression at about 154 ° C and endothermic with a peak at about 157 ° C, and exotherm at about 159 ° C.

In some embodiments, Form A is non-hygroscopic.

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

In some embodiments, Form A is ethyl acetate, isopropylacetone, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole. , Acetone, heptane, methanol / water mixture, or acetone / heptane mixture. In some embodiments, Form A is ethyl acetate, isopropylacetone, 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.

In some embodiments, Form A is solvated. In some embodiments, Form A is anhydrous.

&lt;Compound 1, Form B&gt; In some embodiments, compound 1 is crystalline. In some embodiments, compound 1 is crystalline form B. Crystal form B of compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, much the same as that shown in Figure 5; (b) 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, X-ray powder diffraction (XRPD) pattern; (c) Approximately the same X-ray powder diffraction (XRPD) pattern after storage at 40 ° C and 75% RH for at least 1 week; (d) at least 1 week, 25 ° C And about the same X-ray powder diffraction (XRPD) pattern after storage at 97% RH; (e) infrared (IR) spectrum, much like that shown in Figure 6; (f) about 1586 cm^-1, About 1573 cm^-1, About 1562 cm^-1, About 1229 cm^-1, About 1141 cm^-1, About 1103 cm^-1, About 1056 cm^-1, And about 1033 cm^-1Weak peaks in the infrared (IR) spectrum at; (g) DSC thermograms similar to those shown in Figure 7; (h) Thermogravimetric analysis (TGA) thermograms similar to those shown in Figure 8. (i) DSC thermogram with expression at about 99-106 ° C and heat absorption with a peak at about 115-118 ° C; (j) observed at about 0.0096 mg / mL at about pH 7.42 Water solubility; or (k) a combination thereof.

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

In some embodiments, embodiment B has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, embodiment B is 5.2 ± 0.1 ° 2-seater, 10.2 ± 0.1 ° 2-seater, 16.5 ± 0.1 ° 2-seater, 18.5 ± 0.1 ° 2-seater, and 20.8 ± 0.1 ° 2-. It has an X-ray powder diffraction (XRPD) pattern with characteristic peaks in theta. In some embodiments, Form B has approximately 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 approximately the same X-ray powder diffraction (XRPD) pattern after storage at 25 ° C and 97% RH for at least 1 week.

In some embodiments, embodiment B has an infrared (IR) spectrum similar to that shown in FIG. In some embodiments, Form B is about 1586 cm.^-1, About 1573 cm^-1, About 1562 cm^-1, About 1229 cm^-1, About 1141 cm^-1, About 1103 cm^-1, About 1056 cm^-1, And about 1033 cm^-1Has a weak peak in the infrared (IR) spectrum at.

In some embodiments, embodiment B has a DSC thermogram that closely resembles that shown in FIG. In some embodiments, embodiment B has a thermogravimetric analysis (TGA) thermogram that closely resembles that shown in FIG. In some embodiments, embodiment B has a DSC thermogram with an endothermic expression at about 99-106 ° C and a peak at about 115-118 ° C.

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

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

In some embodiments, Form B is solvate. In some embodiments, form B is anhydrous.

&lt;Compound 1, Form C&gt; In some embodiments, Compound 1 is crystalline. In some embodiments, compound 1 is crystalline form C. Crystal form C of compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, much the same as that shown in Figure 9; (b) 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 ± X-ray powder diffraction (XRPD) pattern with characteristic peaks at 0.1 ° 2-theta, 22.1 ± 0.1 ° 2-theta, and 22.9 ± 0.1 ° 2-theta; (c) as shown in Figure 10. DSC thermograms similar to (d) Thermogravimetric analysis (TGA) thermograms similar to those shown in Figure 11; (e) Expression at about 99-106 ° C and at about 115-118 ° C DSC thermograms with heat absorption with peaks; or (f) combinations thereof.

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

In some embodiments, embodiment C has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, embodiment C is 7.0 ± 0.1 ° 2-seater, 14.0 ± 0.1 ° 2-seater, 15.7 ± 0.1 ° 2-seater, 18.2 ± 0.1 ° 2-seater, 19.1 ± 0.1 ° 2-seater. X-ray powder diffraction (XRPD) with characteristic peaks at, 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. Has a pattern.

In some embodiments, embodiment C has a DSC thermogram that closely resembles that shown in FIG. In some embodiments, embodiment C has a thermogravimetric analysis (TGA) thermogram that closely resembles that shown in FIG. In some embodiments, embodiment C has a DSC thermogram with an endothermic expression at about 134-135 ° C and a peak at about 137-139 ° C.

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

In some embodiments, Form C is solvated. In some embodiments, Form C is anhydrous.

&lt;Compound 1, Form D&gt; In some embodiments, compound 1 is crystalline. In some embodiments, compound 1 is crystalline form D. Crystal form D of compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, much the same as that shown in Figure 12; (b) 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 ± X-ray powder diffraction (XRPD) pattern with characteristic peaks at 0.1 ° 2-theta, 21.0 ± 0.1 ° 2-theta, 21.9 ± 0.1 ° 2-theta, and 22.4 ± 0.1 ° 2-theta; c) Thermoweight analysis (TGA) thermograms similar to those shown in Figure 13; or (d) combinations thereof.

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

In some embodiments, embodiment D has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, embodiment D is 7.2 ± 0.1 ° 2-seater, 8.0 ± 0.1 ° 2-seater, 9.2 ± 0.1 ° 2-seater, 14.5 ± 0.1 ° 2-seater, 18.5 ± 0.1 ° 2-seater. , 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 with characteristic peaks. , Has an X-ray powder diffraction (XRPD) pattern.

In some embodiments, embodiment D has a thermogravimetric analysis (TGA) thermogram that closely resembles that shown in FIG.

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).

&lt;Compound 1, Form E&gt; In some embodiments, compound 1 is crystalline. In some embodiments, compound 1 is crystalline form E. Crystal form E of compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, much the same as that shown in FIG. 14; (b) 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 ± X-ray powder diffraction (XRPD) pattern with characteristic peaks at 0.1 ° 2-theta, 21.6 ± 0.1 ° 2-theta, and 25.2 ± 0.1 ° 2-theta; (c) as shown in Figure 15. DSC thermograms that are similar to; (d) Thermogravimetric analysis (TGA) thermograms that are similar to those shown in Figure 15; or (e) combinations thereof.

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

In some embodiments, embodiment E has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, embodiment E is 7.8 ± 0.1 ° 2-seater, 8.8 ± 0.1 ° 2-seater, 16.1 ± 0.1 ° 2-seater, 18.1 ± 0.1 ° 2-seater, 19.3 ± 0.1 ° 2-seater. X-ray powder diffraction (XRPD) with characteristic peaks at, 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. Has a pattern.

In some embodiments, embodiment E has a DSC thermogram that closely resembles that shown in FIG. In some embodiments, embodiment E has a thermogravimetric analysis (TGA) thermogram that closely resembles that shown in FIG.

In some embodiments, Form E was obtained from toluene.

In some embodiments, Form E is solvated. In some embodiments, Form E is solvated with toluene.

&lt;Compound 1, Form F&gt; In some embodiments, Compound 1 is crystalline. In some embodiments, compound 1 is in crystalline form F. The crystalline form F of compound 1 is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, much the same as that shown in FIG. 16; (b) 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 ° X-ray powder diffraction (XRPD) pattern with characteristic peaks at 2-theta and 29.3 ± 0.1 ° 2-theta; (c) 100 (2) K unit cell parameters approximately equal to: ::

<tables num="3"><img file="JP2020015744A_D0004.tif" /></tables>

Or (d) a combination thereof.

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

In some embodiments, embodiment F has an X-ray powder diffraction (XRPD) pattern similar to that shown in FIG. In some embodiments, embodiment F is 6.2 ± 0.1 ° 2-seater, 10.1 ± 0.1 ° 2-seater, 17.6 ± 0.1 ° 2-seater, 18.6 ± 0.1 ° 2-seater, 20.0 ± 0.1 ° 2-seater. , 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 It has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at ± 0.1 ° 2-theta, 27.6 ± 0.1 ° 2-theta, and 29.3 ± 0.1 ° 2-theta.

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

<tables num="4"><img file="JP2020015744A_D0005.tif" /></tables>

In some embodiments, Form F was obtained from methanol.

In some embodiments, Form F is solvated. In some embodiments, Form F is solvated with methanol.

&lt;Preparation of Crystal Form&gt; In some embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1- Crystal forms of i) piperidine-1-yl) prop-2-en-1-one are prepared as outlined in the Examples. Note that the solvents, temperatures, and other reaction conditions presented herein can vary.

&lt;Appropriate solvent&gt; Therapeutic agents that can be administered to mammals such as humans must be prepared in accordance with regulatory guidelines. Such government-regulated guidelines are called Good Manufacturing Practices (GMP). GMP guidelines describe acceptable levels of contamination of active therapeutic agents, such as the amount of residual solvent in the final product. The preferred solvent is suitable for use in GMP facilities and is in harmony with industrial safety concerns. The categories of solvents are, for example, at 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). It is defined.

Solvents fall 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 agents. Class 3 solvents are considered low toxicity and are of lower risk to human health. Data on Class 3 solvents show that they are less toxic in acute or short-term studies and negative in genotoxicity studies.

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

Examples of Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, 1,2-dimethoxyethane, N, N-dimethylacetamide, N, N-dimethyl. Formamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidin, nitromethane, pyridine, sulfolane, tetraline, toluene, 1,1,2-Trichloroethane, and xylene.

Class 3 solvents with low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethylsulfoxide, ethanol, acetic acid. Ethyl, ethyl ether, ethyl formate, formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentan, 1-pentanol, 1-Propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

The residual solvent in the active pharmaceutical ingredient (API) results from the manufacture of the API. In some cases, the solvent is not completely removed by actual production techniques. Appropriate selection of solvents for the synthesis of APIs may increase yields or determine properties such as crystal form, purity, and solubility. Therefore, solvent is a crucial parameter in the synthetic process.

In some embodiments, the composition comprising compound 1 comprises an organic solvent. In some embodiments, the composition comprising compound 1 comprises a residual amount of organic solvent. In some embodiments, the composition comprising Compound 1 comprises a residual amount of Class 3 solvent. In some embodiments, the active agent is a class 3 solvent. In some embodiments, the class 3 solvent is 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 , Bupropyl acetate, and tetrahydrofuran. In some embodiments, the class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

&lt;Specific terminology&gt; 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 above general description and the following detailed description are typical and exemplary only and do not limit any claimed content. In this application, the use of the singular includes the plural unless otherwise stated. As used in the specification and the accompanying claims, the singular forms "a", "an", and "the" include multiple directed targets unless explicitly stated otherwise. You have to be careful. In this application, the use of "or" means "and / or" unless otherwise stated. Furthermore, the use of the term "including" is unrestricted, as is the case with other forms such as "include", "includes", and "included".

The section titles used herein are for constitutive purposes only and are not construed as limiting the subject matter described. All documents, including but not limited to patents, patent applications, treatises, books, manuals, and editorials, or any part of a document, is made clear herein by citation in its entirety for any purpose. Be incorporated.

As used herein, with respect to a formulation, composition, or ingredient, the terms "acceptable" or "pharmaceutically acceptable" are sustained for the overall health of the subject being treated. It means that it does not exert any harmful effects or does not suppress the biological activity or properties of the compound and is relatively non-toxic.

As used herein, the term "agonist" refers to a compound whose presence is the same as the biological activity resulting from the presence of a naturally occurring ligand for a protein, eg, Btk. The result is the biological activity of the protein.

As used herein, the term "partial agonist" refers to a compound, the presence of which is of the same type as resulting from the presence of a naturally occurring ligand for a protein, but to a lesser extent. , The resulting biological activity of the protein.

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

As used herein, the "improvement" of a particular disease, disorder, or symptom of a particular disease by administering a particular compound or pharmaceutical composition is due to or related to the administration of the compound or composition. What you get is to reduce the severity, delay the onset, slow the progression, or shorten the duration, either permanently, temporarily, long-term, or short-term.

"Bioavailability" refers to the percentage of compound 1 administered that is delivered to the systemic circulation of the animal or human being studied. Total exposure of the drug when administered intravenously (AUC)_(0-∞)) Is usually defined as 100% available to living organisms (F%). "Oral bioavailability" refers to the extent to which Compound 1 is absorbed into the systemic circulation when the pharmaceutical composition is obtained orally, as compared to intravenous injection.

"Plasma concentration" refers to the concentration of Compound 1 in the plasma component of a subject's blood. It is understood that the plasma concentration of Compound 1 can vary significantly between subjects due to its variability in metabolism and / or possible interaction with other therapeutic agents. According to one embodiment disclosed herein, the plasma concentration of Compound 1 may vary from subject to subject. Similarly, maximum plasma concentration (C_max) Or time to reach maximum plasma concentration (T_max), Or plasma concentration time curve (AUC)_(0-∞)The total area under) may vary from subject to subject. Due to this variability, the amount required to construct a "therapeutically effective amount" of Compound 1 may vary from subject to subject.

As used herein, the term "Bruton's tyrosine kinase" refers to Bruton's tyrosine kinase from Homo sapiens, eg, as disclosed in US Pat. No. 6,326,469 (GenBank Accession No. NP_000052). ..

As used herein, the term "Bruton's tyrosine kinase homologue" refers to the ortholog of Bruton's tyrosine kinase, eg, mouse (GenBank Acession No. AAB47246), dog (GenBank Acession No. XP_549139), rat. Orthologs from (GenBank Acession No. NP_001007799), chickens (GenBank Acession No. NP_989564), or zebrafish (GenBank Acession No. XP_698117), and Bruton's tyrosine kinases (eg, peptide substrates with the amino acid sequence "AVLESEEELYSSARQ"). Refers to any of the fusion proteins described above that exhibit kinase activity on one or more substrates of.

As used herein, the term "co-administration" etc. means to include administration of a selected therapeutic agent to a single patient, the same or different routes of administration, or the same or different administration. It is intended to include a treatment regimen in which the drug is administered over time.

The term "effective amount" or "therapeutically effective amount", as used herein, refers to a drug or compound administered that provides some relief from one or more symptoms of the disease or disease being treated. Represents a sufficient amount. As a result, signs, symptoms, or causes of the disease can be reduced and / or alleviated, or any other desired modification of the biological system can be achieved. For example, in therapeutic applications, an "effective amount" is a composition comprising a compound disclosed herein that is necessary to clinically adequately reduce disease symptoms without causing undue adverse side effects. The amount. An appropriate "effective amount" in any individual can be determined using techniques such as dose-increasing tests. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective in achieving the desired pharmacological effect or therapeutic improvement without causing undue adverse side effects. The "effective amount" or "therapeutically effective amount" is the variation in the metabolism of Compound 1, the subject's age, weight, general condition, the disease to be treated, the severity of the disease to be treated, and the attending physician. It is understood that the judgment can vary from subject to subject. As just one example, a therapeutically effective amount can be determined by routine studies, including but not limited to dose-increasing clinical trials.

The term "enhance" or "enhancing" means to increase or prolong a desired effect, either in potency or duration. As an example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong the effect of a therapeutic agent, either in efficacy or duration, while treating the disease, disorder, or disease. .. As used herein, the term "effective amount for augmentation" refers to an amount appropriate to enhance the efficacy of a therapeutic agent in the treatment of a disease, disorder, or disease. When used in patients, the amount effective for this application depends on the severity and course of the disease, disorder, or disease, previous treatment, patient health and response to the drug, and the judgment of the treating physician.

As used herein, the term "family cysteine" refers to a cysteine residue found at a sequence position cognate with cysteine 481 in Bruton's tyrosine kinase, as defined herein. For example, cysteine 482 is a family cysteine of the Bruton's tyrosine kinase rat ortholog; cysteine 479 is a family cysteine of chicken ortholog; and cysteine 481 is a family cysteine of zebrafish ortholog. In another example, a member of the Tec kinase family associated with the TXK family cysteine, Bruton's tyrosine, is cysteine 350. Another example of a kinase having a cognate cysteine is shown in FIG. See also the tyrosine kinase (TK) sequence alignment published on the World Wide Web at kinase.com/human/kinome/phylogeny.html.

As used herein, the term "identical" refers to two or more sequences or subsequences that are identical. Further, as used herein, the term "substantially identical" is used when compared and positioned for maximum match by a comparison window, or using a comparison algorithm, or manually. Refers to two or more sequences with a percentage of sequence units, which is the same if you specify a region as measured by alignment and visual inspection by. As just one example, two or more sequences are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical over a region where contiguous units are designated. , About 90% identical, or about 95% identical, can be "substantially identical". Such percentages are meant to describe the "percent identity" of two or more sequences. Sequence identity can be present in contiguous units of at least about 75-100 in length, in contiguous units of about 50 in length, or, unless otherwise specified, over the entire sequence. This definition also refers to the complement of the test sequence. As just one example, if the amino acid residues are the same, the two or more polypeptide sequences are the same, while the amino acid residues are about 60% identical, about 65% identical, about on the designated region. Two or more polypeptide sequences are "substantially identical" when they are 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical. Identity can be present 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, the entire sequence of the polypeptide sequence. In addition, as just one example, if the nucleic acid residues are the same, the two or more polynucleotide sequences are the same, while the nucleic acid residues are about 60% identical, about 65%, on the designated region. When identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical, two or more polynucleotide sequences are "substantially identical." Is. Identity is at least about 75-10 in length

As used herein, with respect to kinases, the terms "inhibit," "inhibit," or "inhibitor" refer to inhibition of the phosphate transferase activity of an enzyme.

As used herein, the term "irreversible inhibitor" causes the formation of new covalent bonds with or within the protein after contact with the target protein (eg, kinase), thereby causing the target protein. Refers to a compound in which one or more of the biological activities (eg, kinase activity) of a protein is reduced or eliminated despite the presence or absence of an irreversible inhibitor.

As used herein, the term "irreversible Btk inhibitor" refers to an inhibitor of Btk that is capable of forming a covalent bond with an amino acid residue of Btk. In one embodiment, the irreversible inhibitor of Btk can form a covalent bond with the cysteine residue of Btk; in certain embodiments, the irreversible inhibitor is the cysteine residue of Btk (or its cognate). It can form a covalent bond with a cysteine residue at the corresponding position of the body) or a family of another tyrosine kinase.

As used herein, the term "separated" refers to the separation and removal of a subject component from a non-target component. The separated material may be in a dry or semi-dry state, or may be present in a solution containing, but not limited to, an aqueous solution. The separated components are in a homogeneous state, or the separated components can be part of a pharmaceutical composition containing additional pharmaceutically acceptable carriers and / or excipients. As just one example, when a nucleic acid or protein does not have at least some of the cellular components that accompany it in its natural state, or when the nucleic acid or protein is concentrated to a level higher than its in vivo or in vitro production concentration. The nucleic acid or protein is "separated". Also, as an example, a gene is separated when it is separated from an open reading frame that is located on the side of the gene and encodes a protein other than the gene of interest.

The term "regulate" means, as used herein, to interact directly or indirectly with a target to alter the activity of the target, and changes in the activity of the target are just one example. However, it includes 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.

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 scale of a particular activity of a molecule as compared to the scale of activity in the absence of the modulator. In certain embodiments, the modulator is an inhibitor that reduces the magnitude of the activity of one or more of the molecules. In certain embodiments, the inhibitor is an inhibitor that completely prevents the activity of one or more of the molecules. In certain embodiments, the modulator is an activator that increases the magnitude of the activity of one of the molecules. In certain embodiments, the presence of a modulator results in an activity that does not occur in the absence of the modulator.

As used herein, the term "prophylactically effective amount" is the amount of composition applied to a patient that, to some extent, relieves one or more of the symptoms of the disease, disease, or disorder being treated. Point to. In such prophylactic applications, such amounts may depend on the patient's health, weight, etc. Determining such prophylactically effective amounts by routine studies, including but not limited to dose-increasing clinical trials, is well considered to the extent of those skilled in the art.

As used herein, the term "subject" refers to an animal that is the subject of treatment, observation, or experimentation. As just one example, a subject can be, but is not limited to, a mammal, including but not limited to humans.

As used herein, the term "target activity" refers to biological activity that can be regulated by selective modulators. Certain typical targeting activities include, but are not limited to, binding affinity, signal conversion, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and improvement of one or more symptoms associated with the disease or disease. Not limited to these.

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

The terms "treat," "treating," and "treatment," as used herein, reduce, reduce, or ameliorate the symptoms of a disease or illness. To do, to prevent further symptoms, to improve or prevent the underlying cause of the disease, to inhibit the disease or disease, for example, to prevent the disease or the progression of the disease, to prevent the disease or disease. It includes alleviating, regressing a disease or illness, alleviating a disease or condition caused by a disease, or stopping a disease or illness. The terms "treating," "treating," or "treating" include, but are not limited to, prophylactic and / or therapeutic treatment.

IC as used herein₅₀Refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of maximal response, such as inhibition of Btk, in an assay that measures maximal response.

EC as used herein₅₀Refers to the dose, concentration, or amount of a particular test compound that is evoked, triggered, or enhanced by a particular test compound and that elicits a dose-dependent response with up to 50% expression of the particular reaction. ..

Pharmaceutical composition / formulation

The pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, which facilitate the treatment of the active compound into a pharmaceutically usable formulation. Can be done. The appropriate formulation depends on the route of administration chosen. Any of the well-known techniques, carriers, and excipients can be used as appropriate and understood in the art. An overview of the pharmaceutical compositions described herein is, for example, incorporated herein by reference in their entirety, 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, HA It can be found in 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 &amp; Wilkins 1999).

Pharmaceutical compositions, as used herein, contain other chemical components such as carriers, stabilizers, diluents, dispersants, suspensions, thickening stabilizers, and / or excipients. Refers to a mixture of compound 1. The pharmaceutical composition facilitates administration of the compound to mammals. In performing the treatment methods or uses provided herein, a therapeutically effective amount of the compound is administered as a pharmaceutical composition to a mammal having the disease, disorder, or disease being treated. Preferably, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compounds used, and other factors. The compounds may be used alone or in combination with one or more therapeutic agents as components of a mixture.

The term "pharmaceutical formulation", as used herein, means the product resulting from the mixing or combination of more than one active moiety, both fixed and non-fixed formulations of the active ingredient. Including. The term "fixed formulation" means that the active ingredient, eg, both Compound 1 and an adjunct, is co-administered to the patient in the form of a single entity or dosage. The term "non-fixed formulation" means that the active ingredient, eg, Compound 1 and an adjunct, are administered to the patient as separate entities simultaneously, in parallel or in succession, without specific time-limited intervention. However, such administration provides the patient's body with effective levels of the two compounds. The latter is also indicated for cocktail therapy, eg administration of three or more active moieties.

In some embodiments, crystalline compound 1 is incorporated into the pharmaceutical composition to provide a solid oral dosage form. In other embodiments, crystalline compound 1 is used to prepare pharmaceutical compositions other than oral solid dosage forms. The pharmaceutical formulations described herein include, but are limited to, oral, parenteral (eg, intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. It is administered to the subject by multiple routes of administration that are not. The pharmaceutical formulations described herein are aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast-dissolving formulations, tablets, capsules, Includes, but is not limited to, pills, delayed release formulations, extended release formulations, pulsed release formulations, multiplex particulate formulations, and immediate mixing and controlled release formulations.

Pharmaceutical compositions containing the compounds described herein are, by way of example only, means of conventional mixing, dissolving, granulating, dragee manufacturing, grinding, emulsifying, encapsulation, inclusion, or compression processes. It can be manufactured by conventional methods.

&lt;Dosage Form&gt; The pharmaceutical compositions described herein are, but are not limited to, oral, parenteral (eg, intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal administration. It can be formulated for administration to mammals via any conventional means, including routes. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including human or non-human. The terms patient and subject can be used interchangeably.

In addition, the pharmaceutical compositions described herein comprising Compound 1 include, but are not limited to, solid oral dosage forms, controlled release formulations, fast-dissolving formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release. It can be formulated in any suitable dosage form, including formulations, extended release formulations, pulsed release formulations, multiplex particulate formulations, and mixed immediate release and controlled release formulations.

Oral pharmaceutical preparations, if desired, include one or more solid excipients, one or more compounds described herein, after addition of the appropriate auxiliaries to obtain tablets or dragee cores. It can be obtained by mixing with, optionally grinding the resulting mixture, and treating the mixture of granules. Suitable excipients are sugars including, for example, lactose, sucrose, mannitol, or sorbitol; for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanto gum, methyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, Includes fillers such as cellulose preparations such as sodium carboxymethyl cellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, a disintegrant can be added, such as crosslinked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid such as sodium alginate or a salt thereof.

Pharmaceutical preparations that can be used orally include extruded capsules made of gelatin, as well as soft sealed capsules made of gelatin, and plasticizers such as glycerol or sorbitol. Extruded capsules may contain the active ingredient in a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration should be in doses suitable for such administration.

In some embodiments, the solid dosage forms disclosed herein include tablets (including suspension tablets, fast-dissolving tablets, bite-degrading tablets, rapidly disintegrating tablets, effervescent tablets, or capsules), rounds, and powders. Agents (including sterile packaged powders, distributable powders, or foamed powders), capsules (soft or hard capsules, eg capsules made from animal-derived gelatin or plant-derived HPMC, or " Other embodiments may be in the form of "sprinkle capsules", solid dispersants, solid solutions, biodegradable dosage forms, controlled release formulations, pulse release dosage forms, multi-fine particle dosage forms, pellets, berries, or aerosols. In addition, the pharmaceutical formulation is in the form of a powder, and in other embodiments, the pharmaceutical formulation is in the form of tablets, including but not limited to fast-dissolving tablets. In addition, the pharmaceutical formulations described herein are in the form of tablets. , As a single capsule, or as a dosage form of multiple capsules. In some embodiments, the pharmaceutical formulation is administered in 2, 3, or 4 capsules or tablets.

In some embodiments, solid dosage forms (eg tablets, effervescent tablets, capsules) are prepared by mixing particles of compound 1 with one or more pharmaceutical excipients to form a bulk blend composition. To. When referring to these bulk blend compositions as homogeneous, the particles of Compound 1 are composed so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. It means that it is evenly distributed throughout the object. Individual unit dosage forms may also include film coatings that disintegrate after ingestion or contact with diluent. These formulations can be produced by conventional pharmacological techniques.

Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, ( 5) Wet granulation method or (6) Fusion. See, for example, 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 (eg Worcester coating), tangential coating, top spray, tableting, extrusion. And so on.

The pharmaceutically solid dosage forms described herein include compound 1 and compatible carriers, binders, fillers, suspending agents, fragrance additives, sweeteners, disintegrants, dispersants. , Surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizing agents, stabilizers, transdermal absorption promoters, humidifying agents, antifoaming agents, antioxidants, preservatives, or theirs. It may contain one or more pharmaceutically acceptable additives, such as one or more combinations. In yet another embodiment, standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), are used and the film coating is provided around the formulation of Compound 1. In one embodiment, some or all of the particles of compound 1 are covered. In yet another embodiment, some or all of the particles of Compound 1 are microencapsulated. In yet another embodiment, the particles of Compound 1 are not microencapsulated and are not coated.

Suitable carriers for use in the solid dosage forms described herein are, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soybeans. Lecithin, Sodium Chloride, Tricalcium Phosphate, Dipotassium Phosphate, Sodium Stearoyl Lactylate, Caragenin, Monoglyceride, Diglyceride, Pregelatinized Starch, Hydroxypropyl Methyl Cellulose, Hydroxypropyl Methyl Cellulose Acetate Steerate, Sculose, Microcrystalline Cellulose, Lactose Including mannitol and so on.

Suitable fillers for use in the solid dosage forms described herein are, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate. , Dextran, starch, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc. Including

Disintegrants are often used in formulations to release compound 1 from the solid dosage form matrix as efficiently as possible, especially when the dosage form is compressed with a binder. Disintegrants help rupture the dosage form matrix by swelling or capillary action when water is absorbed into the dosage form. Suitable disintegrants for use in solid dosage forms are, but are not limited to, natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or Promogel® or Explotab. Sodium starch glycolate (registered trademark), wood products, methyl crystalline cellulose (eg, Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® ) P100, Emcocel®, Vivacel®, Min Tia® and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, etc. Cross-linked cellulose, such as cellulose, sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, alginates such as alginic acid salts such as alginic acid or sodium alginate, Veegum® HV (aluminum magnesium silicate), etc. Clay, agar, guar, locust bean, kalaya, pectin, or gum such as tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactant, resin such as cation exchange resin, citrus pulp, sodium lauryl sulfate. Includes, such as sodium lauryl sulfate combined with cellulose. In some embodiments provided herein, the disintegrant is natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked. It is selected from the group consisting of crosslinked starches such as carboxymethyl cellulose, crosslinked croscarmellose, sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments provided herein, the disintegrant is croscarmellose sodium.

Binders give stickiness to solid oral dosage forms: for powder-filled capsule formulations, they aid in the formation of thrombosis, which can be filled into soft or hard-shell capsules, and for tablet formulations, they Helps ensure that the tablets remain intact after compression and ensure mixing uniformity prior to the compression or filling process. Suitable materials for use as binders in the solid dosage forms described herein are, but are not limited to, carboxymethyl cellulose, methyl cellulose (eg Methocel®), hydroxypropyl methyl cellulose (eg Hypromellose USP Pharmacoat). -603, Hydroxypropyl Methyl Cellulose Acetate Stealth (Aqoate) HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (eg, Klucel®), ethyl cellulose (eg, Ethocel®), and microcrystalline cellulose (eg, Avicel®), fine Crystalline dextrose, amylose, magnesium aluminum silicate, polysaccharidoic acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacant, dextrin, sucrose (eg Dipac®) ) Such as sugar, glucose, dextrose, sugar honey, mannitol, sorbitol, xylitol (eg Xylitab®), lactose, natural or synthetic gums such as acacia, tragacant, gatch gum, isapol husk mucus, Starch, polyvinylpyrrolidone (eg Povidone (isapol) husk) CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), Karamatsu arabinogalactan, Veegum®, polyethylene glycol, wax, Includes sodium alginate, etc.

Generally, a binding level of 20-70% is used for gelatin capsule formulations filled with powder. The level of use of the binder in the tablet formulation is either direct compression, wet granulation, roller compression, or the use of other excipients such as fillers that can themselves act as moderate binders. ,different. Prescribers in the art can determine the level of binding for a formulation, but the level of binding agent usage up to 70% in tablet formulations is common.

Suitable lubricants or flow promoters for use in the solid dosage forms described herein are, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metals 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 Includes 6000, propylene glycol, sodium oleate, glyceryl behate, glyceryl palmitostearate, glyceryl benzoate, magnesium, or sodium lauryl sulfate. In some embodiments provided herein, the lubricant is stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, And selected from the group consisting of wax. In some embodiments provided herein, the lubricant is magnesium stearate.

Suitable diluents for use in the solid dosage forms described herein are, but are not limited to, sugars (including lactose, sucrose, and dextrin), polysaccharides (including dextrate, and maltodextrin), polyols (including lactose, sucrose, and dextrin). Includes mannitol, xylitol, and sorbitol), cyclodextrin, and the like. In some embodiments provided herein, the diluents are lactose, sucrose, dextrose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, fine. It is selected from the group consisting of crystalline cellulose, fine cellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

The term "water-insoluble diluent" refers to pharmaceuticals such as calcium phosphate, calcium sulfate, starch, modified starch, and microcrystalline cellulose, and fine cellulose (eg, about 0.45 g / cm).³Represents a compound typically used in the formulation of talc, eg, Avicel, powdered cellulose).

Suitable humidifiers for use in the solid dosage forms described herein include, for example, oleic acid, glycerin monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan mono. Includes oleate, polyoxyethylene sorbitan monolaurate, tetraammonium compounds (eg Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium doxate, triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salt, monostearic acid. Includes glycerin, a copolymer of ethylene oxide and propylene oxide, such as Pluronic® (BASF). In some embodiments provided herein, the surfactants are sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salt, glycerin monostearate, ethylene oxide. And propylene oxide copolymers are selected from the group. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

Suitable suspending agents for use in the solid dosage forms described herein are, but are not limited to, polyvinylpyrrolidone (eg, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30), polyethylene glycol (eg, polyvinylpyrrolidone K30). , Polyethylene glycol can have a molecular weight of about 300-6000, or about 3350-4000, or about 7000-5400), vinylpyrrolidone / vinyl copolymer (S630), sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polysorbate 80, Hydroxyethyl cellulose, sodium alginate, gum, eg, tragacant gum, arabic rubber, guar gum, xanthan, including xanthan gum, sugar, cellulose (eg, sodium carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, etc.), polysorbate 80 , Sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

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

It should be understood that there is considerable overlap between the additives used in the solid dosage forms described herein. Therefore, the additives listed above should be obtained solely as typical and, but not limited to, as the type of additive that can be included in the solid dosage forms described herein. .. The amount of such additives can be readily determined by one of ordinary skill in the art according to the particular properties desired.

In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Descriptively, plasticizers are generally high boiling point solids or liquids. Suitable plasticizers can be added 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 ester, polyethylene glycol, glycerol, acetylated glyceride, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sevacinate, stearic acid, stearol, stearate. , And contains castor oil.

Compressed tablets are solid dosage forms prepared by compression of bulk formulations of the above formulations. In various embodiments, compressed tablets designed to dissolve in the mouth contain one or more flavorings. In other embodiments, the compressed tablet comprises 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 (eg, Opadry® coating, or sugar coating). Film coatings containing Opadry® typically vary from about 1% to about 3% of tablet weight. In other embodiments, the compressed tablet comprises one or more excipients.

Capsules can be prepared, for example, by placing a bulk formulation of a formulation of compound 1 inside the capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the formulation is placed in standard gelatin capsules or non-gelatin capsules, such as capsules containing HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, where the capsule can be swallowed in its entirety, or the capsule can be opened and the contents sprinkled into food before meals. In some embodiments, the therapeutic dose is divided into multiple (eg, 2, 3, or 4) capsules. In some embodiments, the entire dose of the formulation is delivered in capsule form.

In various embodiments, the particles of compound 1 and one or more excipients are dried and mixed and compressed into a mass such as a tablet, which mass is less than about 30 minutes, less than about 35 minutes, about after oral administration. To provide a pharmaceutical composition that substantially disintegrates in less than 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, thereby releasing the formulation into gastrointestinal fluid. Has sufficient hardness.

In another embodiment, the dosage form may comprise a microencapsulated formulation. In some embodiments, one or more other compatible materials are present within the microencapsulated material. Typical materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavors, and binders, suspending agents, disintegrants, fillers, surfactants, solubilizers. Includes carrier materials such as agents, stabilizers, lubricants, humidifiers, and diluents.

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 the compound of Compound 1 in vivo.

Typical microencapsulating materials that help delay the release of formulations containing the compounds described herein are, but are not limited to, hydroxypropyl cellulose ether (HPC), such as Klucel® or Nisso HPC,. Low-substituted hydroxypropyl cellulose ether (L-HPC), hydroxypropyl methylcellulose ether (HPMC), such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824 , And Benecel MP843, methyl cellulose polymers such as Methocel®-A, Hydroxypropyl Methyl Cellulose Acetate Steerate Aqoat (HF-LS, HF-LG, HF-MS), and Metolose®, Ethyl Cellulose (EC). ) And mixtures thereof, such as E461, Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA), eg Opadry. AMB, hydroxyethyl cellulose, such as Natrosol®, carboxymethyl cellulose (CMC), such as Aqualon®-CMC, polyvinyl alcohol, and polyethylene glycol copolymers, such as Kollicoat IR®, monoglyceride (Myverol), triglyceride ( KLX), polyethylene glycol, processed food starch, acrylic polymer and mixtures of acrylic polymer with cellulose ether, such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit® Trademarks) L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12. 5, Eudragit® NE30D, and Eudragit® NE Includes 40D, cellulose phthalate acetate, sepifilms, such as a mixture of HPMC and stearic acid, cyclodextrin, and a mixture of these materials.

In yet other embodiments, plasticizers such as polyethylene glycol (eg, PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, PEG 800), stearic acid, propylene glycol, oleic acid, and triacetin are microcapsules. Incorporated into chemical materials. In other embodiments, the microencapsulating material that helps delay the release of the pharmaceutical composition is from the USP or National Pharmaceuticals Collection (NF). In yet another embodiment, the microencapsulating material is Klucel. In yet another embodiment, the microencapsulating material is mesocel.

The microencapsulated compound 1 can be formulated by methods known to those of skill in the art. Such known methods include, for example, spray drying, rotating disk melting processes, hot melt processes, spray cooling methods, fluidized beds, electrostatic deposition, efferent discharge, rotary suspension separation, liquid or solid gases. Includes polymerization, pressure discharge, or spray solvent extraction tanks at the interface. In addition to these, various chemical techniques such as composite coacervation, dissolution evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, insight polymerization, in-liquid drying methods, and desolvation in liquid media are also available. Can be used. In addition, other methods such as roller compression, ejection / spheroidization, coacervation, or nanoparticle coating may be used.

In one embodiment, the particles of Compound 1 are microencapsulated prior to being formulated into one of the above forms. In 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). To.

In other embodiments, the solid dosage formulation of Compound 1 is plasticized (coated) with one or more layers. Descriptively, plasticizers are generally high boiling point solids or liquids. Suitable plasticizers can be added 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 ester, polyethylene glycol, glycerol, acetylated glyceride, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sevacinate, stearic acid, stearol, stearate. , And contains castor oil.

In other embodiments, powdered preparations comprising a formulation with Compound 1 may be formulated to contain one or more pharmaceutical excipients and flavoring agents. Such powders can be formulated, for example, by mixing the formulation with any pharmaceutical excipient to form a bulk blend composition. Additional embodiments also include suspending agents and / or humidifying agents. This bulk mix is evenly subdivided into units in unit dosage form packages or multiple dose packages.

In other embodiments, foaming powders are also prepared according to the present disclosure. Effervescent salts have been used to disperse the drug in water for oral administration. Foaming salts are granules or crude powders containing agents in a dry mixture, usually composed of sodium bicarbonate, citric acid, and / or tartaric acid. When the salts of the compositions described herein are added to water, the acids and bases react to liberate carbon dioxide, thereby causing "foaming". Examples of effervescent salts include, for example, the following components: 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 release of carbon dioxide is 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 higher. Can be used in combination locations.

In some embodiments, the solid dosage forms described herein utilize an enteric-coated delayed release oral dosage form, i.e., an enteric coating to affect the release of the gastrointestinal tract in the small intestine. It can be formulated as an oral dosage form of a pharmaceutical composition as described herein. Enteric dosage forms include compressed, molded, or extruded tablets / features (coated or uncoated) and / or containing the active ingredient granules, powders, pellets, beads, or microparticles. , Other compositional components (which themselves are coated or uncoated). Enteric dosage forms also contain capsules (coated or uncoated) and / or compositions (coated by themselves or) containing solid carrier berries, powders, pellets, beads, or microparticles. Can be uncoated).

As used herein, the term "delayed release" is used in several generally predictable locations in the gastrointestinal tract distal to those achieved in the absence of delayed release changes. Refers to delivery in which release can be achieved. In some embodiments, the method of delaying release is coating. Any coating must be applied in sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluid at a pH of less than about 5, but dissolves at a pH of about 5 or more. It is predicted that any anionic polymer exhibiting pH-dependent soluble properties can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. Will be done. In some embodiments, the polymers described herein are carboxylic acid polymers of anions. In other embodiments, polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to:

Also called shellac or refined rack, it is a refined product obtained from the secretion of resinous substances from insects. This coating dissolves in medium with pH&gt; 7;

Acrylic polymer. The performance of acrylic polymers (mainly 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 methacrylic acid copolymers. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available for solubilization in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble but permeable in the gastrointestinal tract and are primarily used for colon 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;

Cellulose derivative. Examples of suitable cellulose derivatives are: ethyl cellulose; a reaction mixture of a partial acetate of cellulose with phthalic anhydride. Its performance can vary based on the degree and type of substitution. Cellulose phthalate (CAP) dissolves at pH&gt; 6. Aquateric (FMC) is an aqueous-based system, spray-dried CAP pseudolatex with &lt;1 μm particles. Other components in Aquateric may include pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose inductions are: Cellulose Acetate Trimeritate (Eastman); Methyl Cellulose (Pharmacoat, Methocel); Hydroxypropyl Methyl Cellulose Phtalate (HPMCP); Hydroxypropyl Methyl Cellulose Succinate (HPMCS); and Hydroxypropyl Methyl Cellulose Acetator. Cellulose (for example, AQOAT (Shin) Etsu)) is included. Its performance can vary based on the degree and type of substitution. For example, HPMCP (HP-50, HP-55, HP-55S, HP-55F grades, etc.) is appropriate. Its performance can vary based on the degree and type of substitution. For example, the appropriate grade of hydroxypropyl methylcellulose acetate succinate is AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG, which dissolves at higher pH. Including (HF). These polymers are provided as granules or aqueous dispersions; fine powders for polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH&gt; 5, which is less permeable to water vapor and gastric juice.

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

Colorants, detackifiers, surfactants, defoamers, plasticizers (eg, carnuba wax or PEG) were used to solubilize or disperse the coating material, and to solubilize or disperse the coating material, and to perform coating performance and coating. It can be added to the coating in addition to the plasticizer to improve the product.

In other embodiments, the formulations described herein, including Compound 1, are delivered using pulsed dosage forms. The pulse dosage form can provide one or more immediate emission pulses at a predetermined time point after a suppressed delay time or at a particular site. Many other types of controlled release systems known to those of skill in the art are suitable for the application of the formulations described herein. Examples of such delivery systems are polymer-based systems such as, for example, polylactic acid and polyglycolic acid, polyanhydrides, and polycaprolactone; sterol (cholesterol, ester and fatty acid of cholesterol, or neutral fat). Lipids containing (monoglycerides, diglycerides, triglycerides, etc.), porous matrix, non-polymer based systems; hydrogel release systems; silastic systems; peptide based systems; wax coatings, biodegradable dosage forms, Includes compression tablets that use conventional binders and the like. For example, Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., Pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923 See No. 5,516,527, No. 5,622,721, No. 5,686,105, No. 5,700,410, No. 5,977,175, No. 6,465,014, and No. 6,932,983, each of which is specifically incorporated by citation.

In some embodiments, the pharmaceutical formulation is provided containing particles of compound 1, at least one dispersant or suspending agent for oral administration to a subject. The formulation may be a powder or / or granule for suspension, and after mixing with water, a substantially uniform suspension is obtained.

The aqueous dispersions described herein because given additives are often classified differently by different workers in the art or are commonly used for any of a variety of different functions. It is understood that there are overlaps between the additives listed above used in the liquid or suspension. Therefore, the additives listed above should be obtained solely as typical and, but not limited to, as of the type of additive that may be included in the formulations described herein. The amount of such additives can be readily determined by one of ordinary skill in the art according to the particular properties desired.

&lt;Medication and Treatment Regimen&gt; In some embodiments, the amount of Compound 1 administered to a mammal comprises from 300 mg / day to 1000 mg / day. In some embodiments, the amount of Compound 1 administered to the mammal comprises 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 approximately 420 mg / day. In some embodiments, the amount of Compound 1 administered to the mammal is approximately 560 mg / day. In some embodiments, the AUC of compound 1_0-24Is about 150 and about 3500ng^*Between h / mL. In some embodiments, the AUC of compound 1_0-24Is about 500 and about 1100ng^*Between h / mL. In some embodiments, Compound 1 is administered orally. In some embodiments, Compound 1 is administered once daily, twice daily, or three times daily. In some embodiments, Compound 1 is administered daily. In some embodiments, Compound 1 is administered once daily. In some embodiments, compound 1 is administered every other day. In some embodiments, Compound 1 is maintenance therapy.

Compound 1 also includes a subject diagnosed with a hematological malignancies, for inhibition of Btk or its homologues, or for the treatment of a disease or disease in which at least a portion benefits from inhibition of Btk or its homologues. It can be used in the preparation of drugs. In addition, a method for treating any of the diseases or disorders described herein of a subject in need of such treatment is such a method to the subject in a therapeutically effective amount of Compound 1. Or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate. Includes administration of pharmaceutical compositions.

Compositions comprising Compound 1 can be administered for prophylactic, therapeutic, or maintenance treatment. In some embodiments, the composition comprising Compound 1 is administered for therapeutic use (eg, administered to a subject diagnosed with a hematological malignancy). In some embodiments, the composition comprising Compound 1 is administered for therapeutic use (eg, to a subject who is suspected of or is at risk of developing a hematological malignancy). In some embodiments, a composition comprising Compound 1 is administered to a patient in a lull as maintenance therapy.

The amount of compound 1 depends on its use (eg, therapeutically, prophylactically, or maintenance). The amount of Compound 1 depends on the severity and course of the disease or illness, previous treatment, patient health, weight, and responsiveness to the drug, as well as the judgment of the treating physician. Determining such therapeutically effective amounts by routine trials (including, but not limited to, dose-increasing clinical trials) is well considered to the extent of those skilled in the art. In some embodiments, the amount of Compound 1 comprises from 300 mg / day to 1000 mg / day. In some embodiments, the amount of Compound 1 comprises from 420 mg / day to 840 mg / day. In some embodiments, the amount of Compound 1 comprises 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 comprises from 2 mg / kg days to 13 mg / kg / day. In some embodiments, the amount of compound 1 comprises from 2.5 mg / kg days to 8 mg / kg / day. In some embodiments, the amount of compound 1 comprises from 2.5 mg / kg / day to 6 mg / kg / day. In some embodiments, the amount of compound 1 comprises 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.

In some embodiments, the pharmaceutical compositions described herein contain approximately 140 mg of Compound 1. In some embodiments, capsule formulations containing about 140 mg of Compound 1 are prepared. In some embodiments, 2, 3, 4, or 5 capsule formulations are administered daily. In some embodiments, 3 or 4 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, the capsules are administered once daily. In other embodiments, the capsules are administered multiple times per day.

In some embodiments, Compound 1 is administered daily. In some embodiments, compound 1 is administered every other day.

In some embodiments, Compound 1 is administered once daily. In some embodiments, Compound 1 is administered twice daily. In some embodiments, Compound 1 is administered three times daily. In some embodiments, Compound 1 is administered four times daily.

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 individual choice. In some embodiments, Compound 1 is administered every other day until disease progression, unacceptable toxicity, or individual choice.

If the patient's condition improves, administration of the compound may be given continuously, at the discretion of the doctor; alternative, the dose of the drug administered may be temporarily reduced or temporarily reduced for a certain period of time. Can be discontinued (drug holiday). The length of the drug holiday is between 2 days and 1 year (just one example: 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) obtain. Dose reduction during drug holidays is 10% -100% (only, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, Including 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%).

Once improvement of the patient's illness occurs, maintenance doses are administered if necessary. Subsequently, the dose and / or frequency of administration is reduced to a level that sustains improvement of the disease, disorder, or disease, depending on the symptoms. However, patients require long-term intermittent treatment after the recurrence of any symptom.

The amount of drug given, corresponding to such an amount, depends on factors such as the particular compound, the severity of the disease, and the identity (eg, body weight) of the subject or host in need of treatment. Different, but nevertheless, depending on the environment in a manner known in the art, depending on the particular circumstances surrounding, for example, the particular agent administered, the route of administration, and the subject or host being treated. Can be determined on a daily basis. However, in general, the doses utilized for the treatment of adult humans are typically in the range of 0.02-5000 mg per day, or 1-1500 mg per day. The desired dose may be administered as a single dose or simultaneously (or over a short period of time), or as a subdose at appropriate intervals, such as twice, three, four, or more times a day. It can be conveniently provided in divided doses.

The pharmaceutical compositions described herein may be in unit dosage form suitable for a single dose of the correct dose. In the unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. Unit administration is in the form of a package containing discrete amounts of the formulation. Unrestricted examples are packaged tablets or capsules, and powders in vials or ampoules. The aqueous suspension composition can be packaged in a single dose non-resealable container. Alternatively, resealable containers for multiple doses are used, in which case it is common to include a preservative in the composition. By way of example, formulations for parenteral infusion may be provided in unit dosage forms, including but not limited to ampoules, or in multi-dose containers with additional preservatives. In some embodiments, each unit dosage form comprises 140 mg of Compound 1. In some embodiments, the individual is administered one unit dosage form per day. In some embodiments, the individual is administered two unit dosage forms per day. In some embodiments, the individual is administered three unit dosage forms per day. In some embodiments, the individual is administered four unit dosage forms per day.

Due to the large number of variability for individual treatment regimens, the aforementioned ranges are merely suggestive, and considerable range of motion from these recommendations is not uncommon. Such dosages include the activity of the compound used, the disease or disease to be treated, the form of administration, the requirements of the individual subject, the severity of the disease or disease to be treated, and the judgment of the physician. However, it can be changed depending on many variables not limited to these.

The toxicity and therapeutic effects of such treatment regimens are LD₅₀(50% lethal dose of population) and ED₅₀It can be determined by standard pharmaceutical procedures in cell cultures or laboratory animals, including but not limited to determination of (therapeutically effective doses in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, LD₅₀And ED₅₀Can be expressed as a ratio between. Compounds that show a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used to formulate different ranges of doses for use in humans. The dose of such compound is preferably ED with minimal toxicity.₅₀Within a series of blood levels, including. Dose may vary within this range depending on the dosage form utilized and the route of administration utilized.

&lt;Combination therapy&gt; In certain cases, it is appropriate to administer Compound 1 in combination with another therapeutic agent.

In one embodiment, the compositions and methods described herein are also used in combination with other therapeutic reagents selected for their specific utility for the disease being treated. used. In general, the compositions and other agents described herein and in embodiments where combination therapies are used need not be administered in the same pharmaceutical composition and have different physical and chemical characteristics. Therefore, it does not need to be administered by different routes. In one embodiment, the initial dosing is performed according to an established protocol, after which the dose, method of dosing, and number of dosings are further modified based on the observed effects.

In various embodiments, the compounds are simultaneous (eg, at the same time, approximately simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, the disease of the patient, and the actual choice of compound used. , Administered. In certain embodiments, the order of administration during the treatment protocol, and the order of administration of each therapeutic agent and the number of repetitions of administration during the therapeutic procedure of administration of each therapeutic agent, are of the disease being treated. Based on assessment and assessment of patient symptoms.

With respect to the combination therapies described herein, the dose of the co-administered compound depends on the type of co-drug utilized, the particular drug utilized, the disease or disease being treated, and the like. It's different.

The individual compounds in such a combination are administered separately or in combination in a pharmaceutical formulation, continuously or simultaneously. In one embodiment, the individual compounds are administered simultaneously in the combined pharmaceutical formulation. Appropriate doses of known therapeutic agents will be evaluated by those skilled in the art.

The combinations referred to herein are conveniently provided for use in the form of pharmaceutical compositions with both pharmaceutically acceptable diluents or carriers.

The present specification discloses, in a particular embodiment, a method of treating a cancer in an individual in need, which method comprises administering an amount of Compound 1 to the individual. In some embodiments, the method further comprises the step of applying a second cancer treatment regimen.

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

In some embodiments, the second cancer treatment regimen comprises a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted treatment, 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, CD79B inhibitor, CD19 inhibitor, Lyn inhibitor, Syk inhibitor, PI3K inhibitor, Blnk inhibitor, PLCγ inhibitor, PKCβ inhibitor. Agents, or combinations thereof. In some embodiments, the second cancer treatment regimen is an antibody, B cell receptor signaling inhibitor, PI3K inhibitor, IAP inhibitor, mTOR inhibitor, radioimmunotherapeutic, DNA damaging agent, proteosome inhibition. Agents, Cyp3A4 inhibitors, histone deacetylase inhibitors, protein kinase inhibitors, harine mouse inhibitors, Hsp90 inhibitors, telomerase inhibitors, Jak1 / 2 inhibitors, protease inhibitors, PKC inhibitors, PARP inhibitors, or them. It is a combination of.

In some embodiments, the second cancer treatment regimen is chlorambucil, ifosfamide, doxorubicin, mesalazine, salidamide, lenalidomide, temsirolimus, everolimus, fludalabine, hostamatinib, paclitaxel, docetaxel, offaxomab, docetaxel, offatsumab. Includes -101, ifosfamide, tocitsumomab, bortezomib, pentostatin, endostatin, or a combination thereof.

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

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

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

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

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

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

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 epoxy ketone. In some embodiments, the second cancer treatment comprises epoxomicin. In some embodiments, the second cancer treatment comprises a tetrapeptide epoxy ketone. In some embodiments, the second cancer treatment comprises carfilzomib. In some embodiments, the second cancer treatment comprises disulflam, epigallocatechin-3-gallate, salinosporamide A, ONX 0912m CEP-18770, MLN9708, or MG132.

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.

In some embodiments, the second cancer treatment comprises a Janus kinase (JAK) inhibitor. In some embodiments, the second treatment comprises restaultinib, tofacitinib, ruxolitinib, CYT387, baricitinib, or pacritinib.

In some embodiments, the second cancer treatment comprises a histone deacetylase inhibitor (HDAC inhibitor, HDI). In some embodiments, the second cancer treatment is hydroxamic acid (or hydroxamate), such as trichostatin A, vorinostat (SAHA), benzamide (PXD101), LAQ824, and panobinostat (LBH589), cyclic tetrapeptides such as trapoxin. Includes B, depsipeptides, benzamides such as entinostat (MS-275), CI994, and mocetinostat (MGCD0103), electrophilic ketones, or fatty acid compounds such as phenylbutyrate, and valproic acid.

Additional cancer treatment regimens include, for example, nitrogen mustards such as bendamstin, chlorambusyl, chlormethin, cyclophosphamide, iphosphamide, melfaran, prednimastin, tophosphamide; alkyl sulfonates such as vinblastine, mannosulfan, temozolomide; Ethyleneimine such as carbocon, thiotepa, triadicon; nitrosourea such as carmustin, hotemustine, romustine, nimustin, ranimustin, semstin, streptozocin; epoxides such as etoglucid; other alkylating agents such as dacarbazine, mitobronitol, pipobroman, temozolomide Folic acid analogs such as methotrexate, permetrexed, pralatrexate, larcitrexed; purine analogs such as cladribine, clofarabine, fludalabine, mercaptopurine, neralabin, thioguanine; eg azacitidine, capecitabin, carmofur, citarabin Pyrimidine analogs such as gemcitabine, tegafur; vinblastine, vincristine, vincristine, vinflunin, binorelvin, etc., vinca alkaloids; podophylrotoxin derivatives, such as etopocid etoglucid; colhitin derivatives, such as demecortin; Taxan such as mex; other plant alkaloids and natural products such as trabectedin; actinomycin such as dactinomycin; eg acralubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxanthrone, pirarubicin, barrubicin, zorubincin, etc. Anthracyclin; other cytotoxic antibiotics such as bleomycin, ixavepyrone, mitomycin, temozolomide; platinum compounds such as carboplatin, cisplatin, oxaliplatin, satraplatin;Methylhydrazines such as procarbazine; sensitizers such as aminolevulinic acid, ephaproxial, methylaminolevulinate, porphymer sodium, temoporfin; eg dasatinib, ellotinib, everolims, gefitinib, imatinib, lapatinib, nirotinib, pazopanib Protein kinase inhibitors such as sorafenib, snitinib, temsirolimus; eg alitretinoin, altretamine, amzacrine, anagrelide, arsenic trioxide, asparaginase, bexaloten, bortezomib, selecoxib, deniroykindiftix, estramstin Other antitumor agents such as irinotecan, lonidamine, massoprocol, miltefosein, mitoguazone, mitotan, oblimersen, pegaspargase, pentostatin, lomidepsin, citimagene seradenobeck, thiazofulin, topotecan, tretinoin, bortezomib; Estrogen such as diethylstilbenol, ethynyl estradiol, phosfestol, polyestradiol phosphate; progestogens such as guestnolone, medroxyprogesterone, megestrol; for example, buserelin, gosereline, leuprorelin, triptorelin Gonadotropin-releasing hormone analogs such as; anti-estrogens such as fulvestrant, tamoxyphene, tremiphen; eg bicalutamide, flutamide, niltamide, enzyme inhibitors, aminoglutetimide, anastrozole, exemethan, formestane, letrozole, borotezomib Anti-androgen; other anti-hormonal substances such as avalerix, degarelix; immunostimulators such as histamine dihydrochloride, mifamultide, pidotimodo, prelixaform, lokinimex, thymopentin;Immunosuppressants such as everolimus, gusperimus, leflunomide, mycophenolic acid, sirolimus; calcinurin inhibitors such as cyclosporine, tacrolimus; other immunosuppressants such as azathioprine, ixavepyrone, methotrexate, salidamide; and, for example, iobenguan. Includes radiopharmaceuticals.

Additional cancer treatment regimens include interferon, interleukin, tumor necrosis factor, growth factors and the like.

Additional cancer treatment regimens include immunostimulators such as Ancestim, Philgrastim, Lenograstim, Morgramostim, Pegfilgrastim, Salgramostim; eg Natural Interferon Alpha, Interferon Alpha-2a, Interferon Alpha-2b, Interferon Alphacon- 1, interferon alpha-n1, natural interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, peg interferon alpha-2a, peg interferon alpha-2b and other interferons; for example, aldesroykin, oprelbekin and other interferon; For example, BCG vaccine, glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamultide, pegademase, pidotimodo, prelixafor, poly I: C, poly ICLC, rokinimex, tasonermin, thymopentin, etc. Immunostimulators of Immunosuppressants such as mycophenolic acid, natalizumab, sirolimus; TNF alpha inhibitors such as adalimumab, aferimomab, sertrizumab pegor, etanercept, gorimumab, infliximab; , Interferon inhibitors such as ustequinumab; calcinurin inhibitors such as cyclosporin, tachlorimus; and other immunosuppressants such as azathiopurine, renalidemid, methotrexate, salidamide.

Additional cancer treatment regimens include adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, celtrizumab pegor, dacrizumab, eculizumab, efarizumab, gemtuzumab, ibritsumomabuchiuximab, infliximab, ibrituximab, natalizumab , Toshitsumomab, trastuzumab, or a combination thereof and the like.

Additional cancer treatment regimens include, for example, alemtuzumab, basiliximab, katsumakisomab, setuximab, edrecolomab, gemtuzumab, offatumumab, panitumumab, rituximab, trussumab, immunosuppressants, eculizumab, efarizumab, immunosuppressant, eculizumab, efarizumab, , Sertrizumab Pegor, Golimumab, Infliximab, Interleukin Inhibitors, Basiliximab, Kanaquinumab, Dacrizumab, Mepolizumab, Tosirizumab, Ustequinumab, Radiopharmaceuticals, Ibritzomabuchiuxetan, Toshitsumomab and other TNF alpha inhibitors;Avagobomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab, arcitsumomab, baciliximab, bispecific antibody 2B1, blinatumomab, blinatumomab, blinatumomab Pendetide, sixtumumab, cixutumumab, claudiximab, conatumumab, dasetsuzumab, denosumab, ecrizumab, eplatsumab, eplatsumab, eplatsumab, eplatsumab, ertumaxomab Mabu ozogamicin, grebatumumab, ibritsumomab, ibritsumomab ozogamicin, ipilimumab, lexatumumab, linzzumab, linzzumab, lucatumumab, pamatsuzumab, matsuzumab, miratsumumab, matsuzumab, miratsumumab, matsuzumab, miratsumumab , Ranibizumab, cyprizumab, sonepcizumab, denosumab, toshitsumomab, trastuzumab, tremelimumab, tucotuzumab, selmoloikin, bertuzumab, bizirizumab, borosimib, borosimab, borosimab

Additional cancer treatment regimens include agents that affect the tumor's microenvironment, such as cellular signaling networks (eg, phosphatidylinositol 3-kinase (PI3K) signaling pathways, signaling from B cell and IgE receptors). including. 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, enzastaurin and the like.

Examples of agents that affect the microenvironment of the tumor are PI3K signaling inhibitors, syc kinase inhibitors such as dasatinib, elrotinib, everolims, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, temcilim. Protein kinase inhibitors; other angiogenesis inhibitors such as GT-111, JI-101, R1530; eg AC220, AC480, ACE-041, AMG 900, AP24534, Arry-614, AT7519, AT9283, AV- 951, axitinib, AZD1152, AZD7762, AZD8055, AZD8931, bafetinib, BAY73-4506, BGJ398, BGT226, BI 811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036, dinacilib, lactated dobitinib, E7050, EMD1214063, ENMD-2076, hostamatinib ( fostamatinib) disodium, 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 Btk inhibitor, 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, XL281RO5126766, XL418, XL765 and other kinase inhibitors Including.

Further examples of anti-cancer agents for use in combination with Btk inhibitor compounds include, for example, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, Waltmannin, or LY294002. Includes inhibitors of Mightgen-activated protein kinase signaling; Syk inhibitors; mTOR inhibitors; and antibodies (eg, Ritzan).

Other anti-cancer agents that may be utilized in combination with Btk inhibitor compounds are adriamycin, dactinomycin, bleomycin, vinblastin, cisplatin, ashibicin; acralubicin; acodazole hydrochloride; acronin; adzelesin; aldesroykin; altretamine; ambomycin; amethanetron acetate; Aminoglutetimid; amsacrine; anastrosol; anthramycin; asparaginase; asperlin; azacitidine; azetaper; aztomycin; bachimasat; benzodepa; bicartamide; acodazole hydrochloride; biansafide; biserecin; bleomycin sulfate; Busulfan; cactinomycin; carsterone; carasemido; carvetimer; carboplatin; carmustin; carbisin hydrochloride; carzercin; sedefingal; chlorambusil; cilolemycin; cladribine; chrysnator mesylate; cyclophosphamide; citalabin; dacarbazine; daunorubicin hydrochloride; decitabine; Maplatin; Dezaguamine; Dezaguamine Mecilate; Diazicon; Doxorubicin; Doxorubicin Hydrochloride; Doroxyphene; Droroxyphencitate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflornitin Hydrochloride; Elsamitorcin; Enroplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Elbrozole; Esorbicin Hydrochloride; Estramstin; Sodium Estramstin Phosphate; Etanidazole; Etoposide; Etoposide Phosphate; Etoprin; Fadrosole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fluro-Urasylin Phosphate; Fosquidan; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; iphosphamide; iimofostin;Interleukin Il (including recombinant Interlokin II, or rlL2), Interferon Alpha-2a); Interferon Alpha-2b; Interferon Alpha-n1; Interferon Alpha-n3; Interferon Beta-la; Interferon Gamma-lb; Iproplatin; Ilinotecane Hydrochloride; Lanleochidoacetate; Retrosol; Leuprolidea Setate; Riarozole Hydrochloride; Lometrexate Sodium; Romustin; Losoxanthr hydrochloride; Masoprocol; Maytancin; Mechloretamine Hydrochloride; Megestorol Acetate; Melengeslorol Acetate; Melfalan; Menogaryl; Mercaptopurine; Methotrexate; Methotrexate Sodium; Methotrexate; Methredepa; Mitindomido; Mitocalcin; Mitochromin; Mitodiline; Mitomalcin; Mitomycin; Mitosper; Mitotan; Mitozantron Hydrochloride; Mycophenolic Acid; Nokodazoi; Nogaramperamic Acid; Mycin; pentamastin; pepromycin sulfate; perphosphamide; pipobroman; piposulfan; pyroxanthrone hydrochloride; plicamycin; promethan; porphimer sodium; porphyromycin; prednimastin; procarbazine hydrochloride; promycin; puromycin hydrochloride; pyrazofluin; Ribopurine; Logretimid; Safingal; Saffingal Hydrochloride; Semstine; Simtrasene; Sparphosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromastin; Spiroplatin; Streptnigrin; Streptozocin; Slophenal; Thalysomycin; Tecogalan Sodium; Trexatron Hydrochloride; Temoporfin; Teniposide; Teloxylone; Test lactone; Thiamipurine; Thioguanine; Thiotepa; Thiazofluin; Thirapazamine; Tremiphen Citrate; Trestron Acetate; Tricybilin Phosphate; Trimetrexate;Trimetrexate glucuronate; tryptreline; tubrosole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vincristine; bindecine sulfate; vinepidin sulfate; vinorelbine sulfate; binrelbine sulfate; Vinorelbine sulfate; Borozol; Xeniplatin; Dinostatin; Zorbisin hydrochloride.

Other anti-cancer agents that can be utilized in combination with Btk inhibitor compounds include: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; avilateron; aclarubicin; aquilfurben; adecipenor; adzelesin; aldesroykin; ALL -TK antagonist; Altretamine; Ambamastin; Amidox; Amihostin; Aminolevulinic acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Androglafolide; Angiogenesis inhibitor; Antagonist D; Antagonist G; Antarelix; Anti-dorsalized morphogenesis Protein-1 (anti-dorsalizing morphogenetic) protein-1); anti-androgen, prostate cancer; anti-estrogen; anti-neoplastone; anti-sense oligonucleotide; affidicholine glycinate; apoptosis gene modulator; cell death regulator; aprinoic acid; ara-CDP-DL-PTBA; arginine deaminase Athraculin; Atamestan; Atrimastine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azacetron; Azatoxin; Azatyrosine; Baccatin III derivative; Baranol; Batimastat; BCR / ABL antagonist; Bentotyroline; Benzoylstaurosporin Beta-lactam derivatives; beta-alethin; betaclamycin B; bethuric acid; bFGF inhibitor; bicartamide; bisantren; bisazilysin ylspermin; biansafide; bistraten A; biserecin; breflate; bropyrimin; budotitanium; Potriol; Carhostin C; Campotecin derivative; Canalipox IL-2; Capecitabin; Carboxamide-amino-triazole; Carboxamide triazole; CaRest M3; CARN 700; Cartilage-Derived Inhibitors; Calzersin; Casein Kinase Inhibitors (ICOS); Castanospermin; Secropine B; Cetrorelix; Chlorine; Chloroquinoxalin Sulphonamide; Cicaprost; cis-porphyrin; Cladribine; Chromifene Analog; Corrismycin A; Corrismycin B; Combretastatin A4; Combretastatin analog; Conagenin; Clambescidin 816; Crysnator; Cryptoposidein 8; Cryptophycin A derivative; Krasin A; Cyclopentanthirakines; Cycloplatam; cypemycin; citalabine ocphosphate; cytotoxic factors; cytostatin; dacrizumab; decitabine; dehydrodidemin B; deslorerin; dexamethasone; dexfosdamide; dexrazoxane; dexverapamil; diadicon; 9-Dioxamycin; Diphenylspiromastin; Docosanol; Dracetron; Doxyflulysin; Droroxyphene; Dronabinol; Zuocalmycin SA; Ebselen; Ecomstin; Edelfostin; Edrecolomab; Eflornitin; Elemen; Emitefur; Epirubicin; Epristeride; Estramstin Analogs; Estrogen Inhibitors; Estrogen Antagonists; Ethanidazole; Etoposide Phosphate; Exemestane; Fadrosol; Fazarabine; Fenretinide; Philgrastim; Finasteride; Flabopyridol; Fletuelastin; Frusterone; Fluasterone; Fluorodaurabin Hydrochloride Herringin; Forphenimex; Formestane; Phostriecin; Hotemustin; Gadrinium texapirin; Gallium nitrate; Galositabine; Ganirelix; Zelatinase inhibitor; Gemcitabine; Glutathion inhibitor; Hapsurfam; Helegrin; Hexamethylene bisacetamide; Hypericin;Ivandronic acid; Idalbicin; Idoxyphene; Idratonone; Ilmophosin; Ilmostat; Imidazoacridone; Imikimod; Immunostimulatory peptide; Insulin (eg, growth factor-1 receptor inhibitor, etc.); Interferon agonist; Interferon; Interleukin; Iobenguan; Iododoxorbicin; Ipomereanol, 4-; Iropracto; Ilsogradin; Isobengazole; Isohomogeniderin B; Itacetron; Jaspraquinolide; Kahalalide F; Lameralin-N triacetate; Lanleotide; Reinamycin; Lenograstim; Leptolstatin; Retrosol; Leukemia Inhibitors; Leukocyte Alpha Interferon; Leuprolide + Estrogen + Progesterone; Leuprolerin; Revamisol; Riarozole; Linear Polyamine Analogs; Lipid Oil Disaccharide Peptides; Lipid Platinum Compounds; Lissoclinamide ) 7; Robaplatin; Lombricin; Lometerexol; Ronidamine; Losoxantrone; Robastatin; Loxolibin; Lartotecan; Lutetium texapirin; Lisophylline; Cell lysate peptide; Mytancin; Mannostatin A; Marimastert; Masoprocol; Maspin; Matrilysinase Menogaryl; Melbaron; Metalrelin; Methioninase; Metoclopramide; MIF Inhibitors; Mifepriston; Miltehosin; Mirimostim; Inappropriate Double-stranded RNA; Mitoguazone; Mitraxantrone; Mitomycin Analog; Mitonafide; Mitoxantrone; mophalotene; molgramostim; monoclonal antibody (human placental gland stimulating hormone); monophosphoryl lipid A + myobacteria cell wall sk; mopidamole; multidrug resistance gene inhibitor; treatment based on multiple tumor suppressor genes 1; mustard anticancer drug; Micapelloxide B; Mycobacterium cell wall extract; Miraporon;n-Acetyldinarin; N-Substituted benzamide; Nafarelin; Nagrestip; Naroxone + Pentazocin; Napabin; Nafterpin; Narutograstim; Nedaplatin; Nemorphicin; Niridronic acid; Neutral endopeptidase; Niltamide; Nisamycin; Nitrogen monoxide modulator Nitroxide Antioxidants; Nitrulin; O6-benzylguamine; Octreotide; Oxenone; Oligonucleotides; Onapriston; Ondancetron; Ondancetron; Olacin; Oral Cytokinin Inducer; Olmaplatin; Osateron; Oxaliplatin; Ogusaunomycin; Palaamine; palmitoyl lysoxin; pamidronic acid; panaxitriol; panomiphen; parabactin; pazelliptin; pegaspargase; perdecin; sodium pentosampolisulfate; pentostatin; pentrozole; perflubron; perphosphamide; peryl alcohol; phenadinomycin; acetic acid Phenyl; phosphatase inhibitor; pisibanil; pyrocarpine hydrochloride; pirarubicin; pyritrexim; withaferin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compound; platinum triamine complex; porphimer sodium; porphyromycin; prednison; propyl Bis-acridone; prostaglandin J2; proteasome inhibitor; protein A-based immunomodulator; protein kinase C inhibitor; protein kinase C inhibitor, microalgae; tyrosine phosphatase protein inhibitor; purinucleoside phosphorylase inhibitor; purpurin; Zoloaclysin; pyridoxilated hemoglobin poroxyethylelier conjugate; raf antagonist; larcitrexed; ramosetron; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; demethylated retiptin; renium Re 186 etidronate; lysoxin; ribozyme RII retinamide; logretimid; Rohitzkin;Romultide; Rokinimex; Lavidinone B1; Laboxil; Safingal; Saint Pin; SarCNU; Sarcophytol A; Sargramostim; Sdi 1 Mimetic; Semstin; Senessens Derived Inhibitor 1; Sense oligonucleotide; Signal Transmission Inhibitor; Signal Transmission Modulator; Single Chain Antigen-binding protein; sizophyllan; sobzoxane; sodium borocaptate; sodium phenylacetate; salvarol; somatomedin-binding protein; sonarmin; spulfosic acid; spicamycin D; spiromastin; sprenopentin; spongestatin 1; squaramine; stem cells Inhibitors; Stem cell division inhibitors; Stipamide; Stromelysin inhibitors; Sulfinodin; Overactive vascularly active intestinal peptide antagonists; Saladista; Slamin; Swainsonin; Synthetic glycosaminoglycans; Talimstin; Tamoxyphenmethiodide; Tauromas Tin; Tazarotene; Tecogalan sodium; Tegafur; Telrapirium; Telomerase inhibitor; Temoporfin; Temozoromide; Teniposide; Tetrachlorodecaoxide; Tetrazomin; Salibrustin; Thiocolarin; Thrombopoietin; Thrombopoietin mimetic; Timopoietin receptor Timotrinan; Thyroid stimulating hormone; Stin ethylethioproprin; Tyrapazamine; Titanosene dichloride; Topsentin; Tremiphen; Pluripotent stem cell factor; Translation inhibitor; Tretinoin; Triacetyluridine; Tricybillin; Trimethrexate; Tryptrelin; Tropicetron; Thurosteride; Tyrosine kinase inhibitor; Chilhostin; UBC inhibitor; Ubenimex; Growth inhibitor derived from urogenital sinus; Urokinase receptor antagonist; Vapreotide; Variolin B; Vector system, erythrocyte gene therapy; Veraresol; Veramine; American turis gala; Berteporfin Vinolerubin; Vinzartin; Vitaxin; Borozole; Zanoteron; Xeniplatin; Giraskolb;And diostatin stimalamar.

[00427] Other anti-cancer agents that can be utilized in combination with Btk inhibitor compounds are alkylating agents, anti-metaplastic agents, natural products, or hormones such as nitrogen mustards (eg chlormethine, cyclophosphamide, chlorambucil, etc.), Includes alkyl sulfonates (eg, brusfan), nitrosourea (eg, carmustine, lomustine, etc.), or triazene (such as decarbazine). Examples of antimetabolites include, but are not limited to, folic acid analogs (eg methotrexate), or pyrimidine analogs (eg cytarabine), purine analogs (eg mercaptopurine, thioguanine, pentostatin).

Examples of alkylating agents that can be utilized in combination with Btk inhibitor compounds are nitrogen mustards (eg mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimine and methylmelamine (eg hexamethylmelamine, thiotepa), It includes, but is not limited to, alkyl sulfonates (eg, bursphan), nitrosourea (eg, carmustine, romustine, semustine, streptozosine, etc.), or triazene (such as decarbazine). Examples of antimetabolites include, but are not limited to, folic acid analogs (eg methotrexate) or pyrimidine analogs (eg fluorouracil, floxuridine, cytarabine), purine analogs (eg mercaptopurine, thioguanine, pentostatin).

Examples of anti-cancer agents that act by blocking cells in the G2-M phase with stable microtubules and can be utilized in combination with Btk inhibitory compounds have been marketed, but not limited to: Includes drugs, and drugs under development: 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 (also known as Abbott, E-7010), Altorhyrtins (also known as Altorhyrtin A and Altorhyrtin C), Spongistatins ( Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and also known as Spongistatin 9, Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (Epothilone A, Epothilone B, Epothilone C (as desoxyepothilone A or dEpoA) Also known as), 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 (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (Also known as TZT-1027), LS-4559-P (also known as Pharmacia, LS-4577), LS-4578 (also known as Pharmacia, 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 (also known as BASF, 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 (also known as Ajinomoto, AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, AVE-8062, AVE-8062A) , CS-39-L-Ser.HCI, and also known as RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, T-67, TL) -138067 (also known as TI-138067), COBRA 1 (also known as Parker Hughes Institute, DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (BTO) -956 and also known as DIME), DDE-313 (Parker Hughes) Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt.Sinai School of Medicine, MF-569) (Also known as), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt.Sinai School of Medicine, MF) -191), TMPN (Arizona State University), Banadosen Acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-lAABE (also known as NSC-698666) Cytoskeleton / Mt.Sinai School of Medicine, A-204197 (Abbott), T-607 (also known as Tuiarik, T-900607), RPR-115781 (Aventis), Eluterobin (Desmethyl Eluterobin, Desacetyl Eluterobin, Isoerutellobin) Bin A and Z-Elytherobin, etc.), Caribeocid, Caribeolin, Haricondorin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus) , Taccaronoride A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica) , D-68836 (Asta) Medica, Myoseverin B, D-43411 (also known as Zentalis, D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (SPA-110, trifluoroacetate) Also known as) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin Sodium Phosphate, BPR-OY-007 (National Health Research) Institutes), and SSR-250411 (Sanofi).

If an individual suffers from, or is at risk of, an autoimmune disease, an inflammatory disease, or an allergic disease, compound 1 can be used in any combination with one or more of the following therapeutic agents: immunosuppressants (eg, immunosuppressants). Tacrolimus, cyclosporin, rapamicin, methotrexate, cyclophosphamide, azathiopurine, mercaptopurine, mycophenolic acid, or FTY720), glucocorticoids (eg, prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamsinolone Becromethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (eg salicylate, arylalkanoic acid, diarylpropionic acid, N-arylanthranilic acid, oxycam, coxib , Or sulfonanilide), Cox-2-specific inhibitors (eg, valdecoxyb, selecoxib, or lofecoxib), reflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, TNF -α-binding proteins (eg, infliximab, etanercept, or adalimumab), avatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergic vaccines, antihistamines, anti-leucoliens, beta-agonists, theophylline, or anticholinergic medicine.

&lt;Kits / Products&gt; Kits and products are also described herein for use in the therapeutic methods of use described herein. Such kits are, for example, vials, tubes, and other similar ones, that is, one or more individual elements, such as each container, used in the methods described herein. Includes a hauling device, package, or container that is partitioned to receive the container. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the container is made of various materials such as glass or plastic.

The articles provided herein include packaging materials. Packaging materials used for packaging pharmaceutical products include, for example, US Pat. No. 5,323,907. Pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and selected formulations as well as any packaging material suitable for the intended mode of administration and treatment.

In some embodiments, the compounds or compositions described herein are provided in packages or dispenser devices that may include one or more unit dosage forms containing the active ingredient. The compounds or compositions described herein are packaged alone or with another compound or another ingredient or additive. In some embodiments, the package comprises one or more containers filled with one or more of the components of the pharmaceutical composition. In some embodiments, the packaging comprises a metal or plastic foil such as a blister pack. In some embodiments, the packaging or dispenser device is accompanied by instructions for administration, such as instructions for administration of a compound or composition for treating a tumor disease. In some embodiments, the package or dispenser is accompanied by a notice accompanying the container in the form prescribed by a government agency regulating the manufacture, use, or sale of the drug, which notice is human or It reflects government approval for the form of the drug for administration in animals. In some embodiments, such a notice is, for example, a label approved by the US Food and Drug Administration for the insertion of a prescription drug or approved product. In some embodiments, compositions comprising the compounds described herein, formulated in compatible pharmaceutical carriers, are prepared for the treatment of the indicated disease and placed in appropriate containers. And labeled.

For example, the container optionally comprises compound 1 in the composition or in combination with another agent as disclosed herein. Such kits include identification instructions, labels, or instructions for use in the methods described herein.

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

In one embodiment, the label is on top of the packaging or is attached to the packaging. In one embodiment, if the letters, numbers, or other markings that form the label are affixed, molded, or engraved on the container itself, the label is mounted on the container. The label is attached to the container, for example, if it is present in a receptacle or carrier that holds the container as well. In one embodiment, the label is used to indicate that the content should be used for a particular therapeutic application. Labels also indicate instructions for the use of the contents, such as as described herein.

In certain embodiments, the pharmaceutical composition is provided in a pack or dispenser device comprising one or more unit dosage forms comprising the compounds provided herein. Packs include, for example, metal or plastic foils such as blister packs. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser device is attached with a notice accompanying the container in the form prescribed by a government agency that regulates the manufacture, use, or sale of the drug, which notice is human or It reflects government approval for the form of the drug for administration in animals. Such notices are, for example, labels approved by the US Food and Drug Administration for the insertion of prescription drugs or approved products. In one embodiment, a composition comprising a compound described herein, formulated on a compatible pharmaceutical carrier, is prepared, placed in a suitable container, and placed for the treatment of the indicated disease. Be labeled.

<p> The following ingredients, formulations, processes, and procedures for performing the methods disclosed herein correspond to those described above.</p><p>&lt;Example 1: 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) Preparation of Crystal Form of prop-2-en-1-one (Compound 1)&gt; &lt;Form A-Path 1:&gt; Amorphous compound 1 (ca. 15 mg) was measured and placed in a vial. Solvents [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, Alternatively, 10 volumes (150 μl) of 10% aqueous isopropyl alcohol] were added to the vial. The vial was sealed and placed in a shaker at 50 ° C for 1 hour. When the slurry was obtained, 30 volumes of solvent (600 μl total) were added and then the slurry was returned to 50 ° C. for another hour. If the sample remained as a slurry at this point, no further solvent was added. The solution / slurry was stirred for 1 hour at 50 ° C, then cooled to 0 ° C at 0.1 ° C / min and then held at 0 ° C overnight. When the slurry was obtained, the solid was filtered under vacuum to give compound 1, form A; the solution was returned to ambient temperature for slow evaporation through the pinholes to give compound 1, form A. ..</p><p>&lt;Form A-Route 2:&gt; Add amorphous compound 1 (20 mg) to the vial, followed by solvents [heptane (10 vol), dioxane (1 vol), toluene (10 vol), MTBE (10 vol), DIPE. (10 volumes), anisol (1 volume), ethyl acetate (10 volumes), isopropyl acetate (10 volumes), tetrahydrofuran (1 volume), DCM (1 volume), MIBK (10 volumes), MEK (10 volumes), 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)] It was. Sealed vials were placed in maturation chambers (4 hours respectively, cycles between 50 ° C and ambient temperature) for 5 days before filtering the solids under vacuum to give compound 1, form A.</p><p> 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, which occurred rapidly enough to prevent crystallization, to give amorphous compound 1.</p><p>&lt;Form A-Route 3:&gt; 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 agitation. 72 ml of water was added to a warm solution of dissolved compound 1 over 45 minutes and the internal temperature was maintained at 45 ° C. The solution slowly turned into a slurry, which was stirred at high temperature for 3 hours. Slurry samples were extracted, filtered and dried. The slurry was cooled to room temperature and stirred for at least 16 hours. Another sample of slurry was extracted, filtered and dried. The solids were filtered, washed with a 50 ml mixture of methanol: water 3: 2, and dried on a filter for 40 hours. 9.6 grams of Form A was obtained (melting point: 1st sample ~ 152 ° C, 2nd sample ~ 154 ° C, main lot ~ 154 ° C).</p><p> Form A was also obtained in a similar manner using aqueous acetone, ethanol, and n-propanol.</p><p>&lt;Form B-Route 1:&gt; Compound 1 and Form A (ca. 100 mg) were weighed and placed in a tube and dissolved in methanol (2 ml). The solution was heated to 50 ° C to confirm complete dissolution and then cooled to 5 ° C. Water was added to the solution at 5 ° C (200 μl until the sample became turbid, 1000 μl total). Compound 1, Form C seeds were added immediately after turbidity developed. The slurry was stirred for 1 day at 5 ° C. The aliquots were removed with a pipette for analysis by XRPD and most of the samples were kept in the same condition. XRPD analysis emphasized the low crystallinity of the material, so the sample was held at 5 ° C for an additional 3 days. After this point, reanalysis of the aliquots of the sample revealed that the material had been converted to compound 1, form B. The sample was separated by filtration under vacuum to give compound 1, form B.</p><p>&lt;Form B-Route 2:&gt; Compound 1, Form A (ca. 500 mg) was weighed and placed in a tube and dissolved in methanol (4 ml) at 50 ° C. The solution was cooled to 25 ° C and left in the solution. Water was added until the solution became turbid (at which point 500 μl of water was added, for a total of 2 ml). The slurry was stirred for 10 minutes. The aliquots were pipette removed 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 samples were placed at 5 ° C for 3 days. After this point, another aliquot was pipette removed for XRPD analysis. The rest of the slurry was filtered under vacuum and dried under vacuum overnight at 25 ° C to give compound 1, form B.</p><p>&lt;Form C:&gt; In a clean round bottom flask, 2.0 grams of Compound 1 was suspended in 25 ml of methanol and heated to 50 ° C. A warm solution of dissolved compound 1 was filtered and placed in a clean round bottom flask. The cleaned solution was cooled to room temperature by magnetic stirring. The solution slowly turned into a slurry, which was stirred for 14 hours. The solids were filtered, washed with 5 mL of methanol, dried on a filter for 20 hours and then dried in a vacuum oven at 50 ° C. for 8 hours. 1.4 grams of Form C was obtained (melting point = ~ 132 ° C).</p><p>&lt;Form D:&gt; A dry mixture (ca. 5 mg of each component) was prepared using two of Compound 1, Form A, Form B, or Form C. The slurry made from amorphous compound 1 in MIBK was filtered to obtain a saturated solution. 10 volumes (100 μl) of the saturated solution was added to the dry mixture to prepare a new slurry. The slurry was stored at 5 ° C. for 3 days before filtration under vacuum to give compound 1, form D.</p><p>&lt;Form E:&gt; Amorphous compound 1 (20 mg) was added to the vial, followed by compound 1, form C (ca. 5 mg) seeds. 10 volumes (200 μl) of toluene were added to the vial to prepare a slurry. Vials were sealed and aged for 1 day (4 hours each, cycle between 50 ° C and ambient temperature). Aliquots were pipetted for analysis by XRPD, TGA, and DSC; data were consistent with compound 1, form E. However, after allowing to stand overnight at ambient temperature and drying in vacuum for 1 day at 40 ° C, it was found that this compound was converted to Compound 1, Form A.</p><p>&lt;Form F:&gt; 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. A warm solution of dissolved compound 1 was filtered through a syringe filter and placed in a new clean 20 ml vial to remove charcoal. The cleaned solution was cooled to room temperature. In the absence of agitation, the solution was aged for 1 week when several crystals were observed to form. After another 6 weeks, the bottom of the vial was covered with large crystals. Crystals were maintained under supersaturated methanol solution for analysis.</p><p>&lt;Example 2: X-ray powder diffraction (XRPD)&gt; X-ray powder diffraction patterns were collected by Bruker AXS C2 GAD DS or Bruker AXS D8 diffraction counting.</p><p>&lt;Bruker Ax C2 GADDS&gt; Using Cu Ka radiation (40kV, 40mA), automated XYZ steps, laser video microscope for automatic sample positioning, and HiStar 2D region detector, Bruker AXS Collected by C2 GADDS diffraction counting. X-ray optics consists of a single Gobel multilayer mirror coupled with a 0.3 mm pinhole collimator. Weekly performance inspections using certified standard NIST 1976 Corundum (flat plate). The beam spread (ie, the effective diameter of the X-ray rays on the sample) was approximately 4 mm. A θ-θ continuous scan pattern was used with the sample (20 cm detector distance giving an effective 2θ range of 3.2 ° -29.7 °). Typically, the sample is exposed to X-ray rays for 120 seconds. The software used to collect the data was GADDS for WNT 4.1.16, which analyzed the data and provided it using Diffrac Plus EVA v11.0.0.2 or v13.0.0.2.</p><p> Ambient conditions</p><p> Samples run under ambient conditions were prepared as plate samples using a powder that could be received without polishing. A flat surface was obtained by gently pressing a sample of approximately 1-2 mg onto a glass slide.</p><p>&lt;Non-ambient conditions&gt; Samples performed under non-ambient conditions were placed on a silicon wafer equipped with a thermal conductivity compound. The sample was then heated to a suitable temperature at 10 ° C / min (unless otherwise specified) and then held isothermal for 1 minute before data collection began.</p><p>&lt;Bruker AXS D8 Advance&gt; Cu Ka radiation (40kV, 40mA), θ-2θ goniometer, and V4 opening, receiving slits, Ge monochromator and Lynxeye detector, X-ray powder diffraction pattern Was collected by Bruker D8 diffraction counting. The instrument is validated for its performance using a certified Corundum standard (NIST 1976). The software used to collect the data was Diffrac Plus XRD Commander v2.5.0, and the data was analyzed and presented using Diffrac Plus EVA v11.0.0.2 or v13.0.0.2. The sample was run as a flat sample under ambient conditions, using the powder as received. The sample was gently filled into the cavity and cut into a clean zero background (510) silicon wafer. During the analysis, the sample was rotated in its own plane. The details of data collection are as follows: Angle range: 2 to 42 ° 2θ Step size: 0.05 ° 2θ Collection time: 0.5s / process</p><p>&lt;XRPD on Form A&gt; The X-ray powder diffraction for Form A is shown in Figure 1. Characteristic peaks are 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 -Including Theta.</p><p> Crystallinity was unaffected after 1 week of storage at 40 ° C / 75% RH or 1 week of storage at 25 ° C / 97% RH.</p><p>&lt;XRPD on Form B&gt; The X-ray powder diffraction for Form B is shown 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.</p><p> Crystallinity was unaffected after 1 week of storage at 40 ° C / 75% RH or 1 week of storage at 25 ° C / 97% RH.</p><p>&lt;XRPD on Form C&gt; The X-ray powder diffraction for Form C is shown in Figure 9. The characteristic peaks are 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 -Includes Theta, 20.3 ± 0.1 ° 2-Theta, 22.1 ± 0.1 ° 2-Theta, and 22.9 ± 0.1 ° 2-Theta.</p><p> Crystallinity was unaffected after 1 week of storage at 40 ° C / 75% RH or 1 week of storage at 25 ° C / 97% RH.</p><p>&lt;XRPD on Form D&gt; The X-ray powder diffraction for Form A is shown in FIG. The characteristic peaks are 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. -Includes 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.</p><p>&lt;XRPD on Form E&gt; The X-ray powder diffraction for Form E is shown in FIG. The characteristic peaks are 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 -Includes Theta, 20.5 ± 0.1 ° 2-Theta, 21.6 ± 0.1 ° 2-Theta, and 25.2 ± 0.1 ° 2-Theta.</p><p>&lt;XRPD on Form F&gt; A simulated XRPD pattern was generated for Form F. Mercury CSD v3.1 (CF Macrae et al. J. Appl. Cryst. (2006), 39-3, 453-457) (XRPD pattern setting: CuKα1.54056; Start / End 2/43 2θ °; PWHW (2θ) Using °) 0.1), an XRPD simulated pattern was generated from the single crystal data obtained from Example 3 (cif file). The data was then saved as a raw file. Raw files were processed using Diffrac Plus EVA v.15,0,0,0 to generate a peak table of 2θ ° / intensity (%).</p><p> The X-ray powder diffraction simulated pattern for Form F is shown in FIG. The characteristic peaks are 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, including characteristic peaks.</p><p>&lt;Example 3: Single crystal X-ray diffraction&gt; Single crystal X-ray diffraction data was collected and processed as follows:</p><p><tables num="5"><img file="JP2020015744A_D0006.tif" /></tables></p><p> Form F, at a temperature of approximately 100 (2) K, was characterized by unit cell unit cell parameters approximately equal to:</p><p><tables num="6"><img file="JP2020015744A_D0007.tif" /></tables></p><p>&lt;Example 4: Fourier Transform-Infrared (FTIR)&gt; Data were collected on a Perkin-Elmer Spectrum One equipped with a universal Attenuated Total Reflectance (ATR) sampling accessory. Data was collected and analyzed using Spectrum v5.0.1 software.</p><p> The infrared spectrum of Form A is shown in FIG. The characteristic peak observed in the infrared spectrum of Form A is 1584 cm.^-1, 1240cm^-1, 1147cm^-1, 1134cm^-1, 1099cm^-1, 1067cm^-1, 985cm^-1, And 953 cm^-1Including the peak.</p><p> The infrared spectrum of Form B is shown in FIG. The characteristic peak observed in the infrared spectrum of Form B is 1586 cm.^-1, 1573cm^-1, 1562cm^-1, 1229cm^-1, 1166cm^-1, 1141cm^-1, 1103cm^-1, 1056cm^-1, 1033cm^-1, And 982 cm^-1Including the peak.</p><p>&lt;Example 5: Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)&gt; DSC data were collected on TA Instruments Q2000 with an autosampler at position 50. Heat capacity calibration was performed using sapphire and energy and temperature calibration was performed using certified indium. Typically, each 0.5-3 mg sample in a pinhole aluminum pan was heated from 25 ° C to 300 ° C at 10 ° C / min. Purging of dry nitrogen at 50 ml / min was maintained on the sample unless otherwise stated. Adjusted temperature DSCs were performed using a radical heating rate of 2 ° C / min and a temperature modulation parameter of ± 0.318 60 ° C (amplitude) every 60 seconds (duration). Instrument control software is an advantage of Q Series v2.8.0.392 and Thermal Advantage v4.8.3Q, and data was analyzed using Universal Analysis v4.4A.</p><p> TGA data was collected on the TA Instruments Q500 TGA with an autosampler in 16 positions. The instrument was temperature calibrated using certified alumel and nickel. Typically, each 3-10 mg sample was placed on pre-tarred aluminum DSC and heated from ambient temperature to 350 ° C at 10 ° C / min. Nitrogen purge at 60 ml / min was maintained on the sample unless otherwise stated. Instrument control software is an advantage of Q Series v2.8.0.392 and Thermal Advantage v4.8.3Q, and data was analyzed using Universal Analysis v4.4A.</p><p>&lt;Form A&gt; The DSC and TGA thermograms of Form A are shown in FIGS. 3 and 4, respectively.</p><p> No weight loss was observed. The material is anhydrous.</p><p> At DSC (heating rate: 10 ° C / min or 20 ° C / min), endothermic was observed to develop at about 154 ° C and peak at about 157 ° C. The exothermic peak was observed at 159 ° C.</p><p>&lt;Form B&gt; The DSC and TGA thermograms of Form B are shown in FIGS. 7 and 8, respectively.</p><p> No weight loss was observed. The material is anhydrous.</p><p> At DSC (heating rate: 10 ° C / min or 20 ° C / min), endothermic was observed to develop at about 99-106 ° C and peak at about 115-118 ° C. It was.</p><p>&lt;Form C&gt; The DSC and TGA thermograms of Form C are shown in FIGS. 10 and 11, respectively.</p><p> No weight loss was observed. The material is anhydrous.</p><p> At DSC (heating rate: 10 ° C / min or 20 ° C / min), endothermic was observed to develop at about 134-135 ° C and peak at about 137-139 ° C. It was.</p><p>&lt;Form D&gt; The TGA thermogram of Form D is displayed in FIG.</p><p> A total weight loss of 16.6-17.8%, equivalent to about 1 mol of MIBK, was observed by TGA as one or two steps.</p><p>&lt;Form E&gt; The DSC and TGA thermograms of Form E are shown in FIG.</p><p> A weight loss of 16.5% w / w was observed at TGA associated with two endothermic events at DSCs recorded at 85 ° C (expression) and 151 ° C (expression), which could correspond to the desolvation phenomenon. did.</p><p>&lt;Example 6: Gravimetric Vapor Sorption (GVS)&gt; SMS DVS uses an endogenous hygroscopic analyzer to obtain an isothermal sorption curve and is controlled by DVS endogenous control software v1.0.0.30. did. The sample temperature was maintained at 25 ° C by instrument control. Humidity was controlled by mixing a stream of dry and moist nitrogen, with a total flow rate of 200 ml / min. Relative humidity was measured with a calibrated Rotronic probe (dynamic range of 1.0-100% RH) located near the sample. Sample weight changes (mass relaxation) in response to% RH were constantly monitored with a microbalance (accuracy ± 0.005 mg). Typically, 5-20 mg samples were placed in tarred mesh stainless steel baskets under ambient conditions. Samples were loaded and lowered at 40% RH and 25 ° C (typical room conditions). Moisture-absorbing isotherms were performed (two scans giving one full cycle) as outlined below. Standard isotherms were run over the 0-90% RH range at 10% RH intervals at 25 ° C. DVS Analysis I tried data analysis in Microsoft Excel using Suite v6.0.0.7. Samples were collected after the isotherm was completed and reanalyzed by XRPD.</p><p><tables num="7"><img file="JP2020015744A_D0008.tif" /></tables></p><p>&lt;Form A&gt; The rate of change in mass was &lt;0.3% w / w between 0-90% RH. The material is not hygroscopic. No significant changes were observed in XRPD after GVS analysis.</p><p>&lt;Form B&gt; The rate of change in mass was 2.3% w / w between 0-90% RH. No hysteresis was observed. No significant changes were observed in XRPD after GVS analysis.</p><p>&lt;Example 7: Thermodynamic water solubility&gt; Water solubility was determined by suspending sufficient compound in water to obtain a maximum terminal concentration of 10 mg / ml in the free form of the parent of the compound. The suspension was kept in equilibrium 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 with an appropriate factor, eg 101. A standard solution of approximately 0.25 mg / ml in DMSO was weighed by HPLC. Different volumes of standard, diluted and undiluted sample solutions were injected. Solubility was calculated using the peak area, determined by the integration of peaks found at the same retention time as the major peaks in standard injections.</p><p><tables num="8"><img file="JP2020015744A_D0009.tif" /></tables></p><p> Analysis was performed using ChemStation software vB.02.01-SR1 on an Agilent HP1100 series with a diode array detector.</p><p> The solubility of Form A in aqueous solution at different pH is shown in Table 3.</p><p><tables num="9"><img file="JP2020015744A_D0010.tif" /></tables></p><p> The thermodynamic water solubility of Form B at a pH of 7.42 was determined to be 0.0096 mg / ml.</p><p>&lt;Example 8: Determining Chemical Purity&gt; HPLC analysis was performed on an Agilent HP1100 / 1200 system equipped with a diode array detector using ChemStation software using the methods detailed below.</p><p><tables num="10"><img file="JP2020015744A_D0011.tif" /></tables></p><p> In some embodiments, Form A is more than 95% pure by HPLC analysis. In some embodiments, Form A is more than 96% pure by HPLC analysis. In some embodiments, Form A is more than 97% pure by HPLC analysis. In some embodiments, Form A is more than 98% pure by HPLC analysis. In some embodiments, Form A is more than 99% pure by HPLC analysis. In some embodiments, Form A is more pure than 99.8% by HPLC analysis.</p><p> In some embodiments, Form B is more than 95% pure by HPLC analysis. In some embodiments, Form B is more than 96% pure by HPLC analysis. In some embodiments, Form B is more than 97% pure by HPLC analysis. In some embodiments, Form B is more than 98% pure by HPLC analysis. In some embodiments, Form B is more than 99% pure by HPLC analysis. In some embodiments, Form B is more pure than 97.8% by HPLC analysis. In some embodiments, Form B is more than 99.8% pure by HPLC analysis.</p><p> In some embodiments, Form C is more than 95% pure by HPLC analysis. In some embodiments, Form C is more than 96% pure by HPLC analysis. In some embodiments, Form C is more than 97% pure by HPLC analysis. In some embodiments, Form C is more than 98% pure by HPLC analysis. In some embodiments, Form C is more than 99% pure by HPLC analysis. In some embodiments, Form C is more pure than 99.4% by HPLC analysis.</p><p>&lt;Example 9: Determination of chemical purity&gt; The chiral purity of Compound 1 was determined by using a chiral column of Lux Cellulose-1 by normal phase HPLC. The mobile phase consists of 20% isopropyl alcohol and 80% hexane. 1-(3- (4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-yl) prop-2-en-1-one Enantiomer was detected at 260 nm. In one embodiment, compound 1 is dissolved in a mixture of hexane: IPA = (7: 3) to give a concentration of approximately 0.2 mg / mL and the chiral purity of the sample is analyzed. The content of R enantiomers is determined by peak area standardization of enantiomer peaks and is expressed in weight percent. In some embodiments, the sample of Compound 1 comprises less than 5.0%, less than 4.0%, less than 3.0%, less than 2.0%, or less than 1.0% (S) -isomer. In some embodiments, the sample of Compound 1 contains less than 1.0% of the (S) -isomer.</p><p>&lt;Solid oral dosage form&gt; In some embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1- Il) prop-2-en-1-one crystals are formulated in solid oral dosage form. In some embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1- Il) The crystallinity of prop-2-en-1-one is maintained in the solid oral dosage form. In some embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1- Il) Prop-2-en-1-one crystals are formulated into tablets. In some embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1- Il) Prop-2-en-1-one crystals are prescribed in pills. In some embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1- Il) Prop-2-en-1-one crystals are formulated into capsules. In some embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1- Il) Prop-2-en-1-one crystals are placed in capsules without or with excipients. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals are of form A. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, Crystals of 4-d] pyrimidine-1-yl) piperidine-1-yl) prop-2-en-1-one are in morphology B. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals are of form C. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals are of form D. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals are of form E. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals are of form F. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals 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. is there. Crystals of 4-d] pyrimidine-1-yl) piperidine-1-yl) prop-2-en-1-one are of form D. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals are of form E. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals are of form F. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals 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. is there. Crystals of 4-d] pyrimidine-1-yl) piperidine-1-yl) prop-2-en-1-one are of form D. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals are of form E. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals are of form F. In any of these embodiments, 1-((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 -Il) prop-2-en-1-one crystals 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. is there.</p><p>&lt;Example 10: Capsule Preparation&gt; In one embodiment, a capsule preparation of Compound 1 for administration to humans is prepared with the following components:</p><p><tables num="11"><img file="JP2020015744A_D0012.tif" /></tables></p><p> In some embodiments, the manufacturing process comprises the following steps: the indicated amounts of the components are weighed, mixed together and added to a capsule of appropriate size and close to it. In some embodiments, the capsules are stored at room temperature for extended periods of time before use.</p><p>&lt;Example 11: Immediate Release Tablets&gt; In some embodiments, tablets are prepared with the components described in Table 10.</p><p><tables num="12"><img file="JP2020015744A_D0013.tif" /></tables></p><p> The manufacturing process is typically granulation (dry, wet, or dissolution) or direct compression.</p><p>&lt;Example 12: Safety and Resistance Study of Compound 1 in Chronic Lymphocytic Leukemia&gt; Objective: The objective of this study is to have B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma / diffusely differentiated lymphoma. To establish the safety and optimal dose of Orally administered Compound 1 (420 mg / day) in patients.</p><p> First endpoint: Safety and tolerance of Compound 1 (frequency, severity, and association of adverse events).</p><p> Second endpoint: Evaluation of pharmacokinetics / pharmacodynamics. Tumor response-Overall response rate, as defined by recent guidelines for CLL and SLL (B-cell lymphoma), and duration of response.</p><p> Eligibility: 18+; both genders are eligible.</p><p> Inclusion Criteria: 1. Only for untreated groups: NCI or International Working Men and women aged 65 years with a definitive diagnosis of CLL / SLL in need of treatment for Group Guidelines 11-14. 2. For relapsed / refractory groups only: 18 year old men and women with a definitive diagnosis of relapsed / refractory CLL / SLL who are unresponsive to treatment (ie, 2 for CLL / SLL) The previous treatment of the disease has failed, and at least one regimen must have a purine analog [eg, fludarabine] for a subject with CLL. 3. Weight 40kg. 4. ECOG performance status of 2. 5. If sexually active and able to give birth, consent to the use of contraceptives during the study and for 30 days after the last dose of study drug. 6. Willing to participate in all required assessments and procedures in this research protocol, including swallowing capsules effortlessly. 7. Understand the purpose and dangers of the study and be able to sign and date informed consent and approval of the use of protected health information (according to national and local subject privacy rules).</p><p> Exclusion Criteria: 1. In the opinion of the investigator, a life-threatening illness, condition, which may compromise the safety of the subject, interfere with the absorption and metabolism of PO in Compound 1, or expose the study results to undue risk. Or organ system dysfunction. 2. Any immunotherapy, chemotherapy, radiation therapy, or experimental treatment (corticosteroids for disease-related symptoms are allowed, but before administration of the investigational drug, within 4 weeks prior to the first administration of the investigational drug. Requires a week of rinsing). 3. Involvement of the central nervous system (CNS) by lymphoma. 4. Major surgery within 4 weeks prior to the first dose of study drug. 5. Creatinine&gt; 1.5 x histological upper limit of normal (ULN); total bilirubin&gt; 1.5 x ULN (unless due to Gilbert's disease); and aspartate aminotransferase (AST) or alanine aminotransferase unless disease is associated (ALT)&gt; 2.5 x ULN. 6. Prolonged QT or concomitant use of drugs known to cause torsades de pointe. 7. Left bundle branch block, 2nd degree AV block type II II) Significant screening ECG (ECG) abnormalities, including grade 3 block, bradycardia, and QTc&gt; 470 msec. 8. Lactating or pregnant.</p><p>&lt;Example 13: Safety and efficacy of Compound 1 in subjects with relapsed / refractory mantle cell lymphoma (MCL)&gt; The main purpose of this study is relapsed / with mantle cell lymphoma (MCL). To evaluate the efficacy of compound 1 in refractory subjects. A second objective is to assess the safety of a fixed daily dosing regimen (560 mg / day in capsule form) of Compound 1 in this assembly.</p><p> First endpoint: measuring the number of participants who have a response to compound 1.</p><p> Second endpoint: Measure the number of participants with adverse events as an indicator of safety and durability. Measuring pharmacokinetics to help the body determine how it responds to the study drug. Patients receive reports of results (to measure the number of participants who report results in determining the quality of life related to health).</p><p> Eligibility: 18+; both genders are eligible.</p><p> Inclusion criteria: 18 year old men and women. ECOG performance status of 2. Pathologically confirmed MCL by documenting either overexpression of cyclin D1 or t (11; 14), and a cross section with a maximum diameter of 2 cm and measurable in two vertical dimensions. Diseases that can be measured by imaging. Document the failure to achieve at least partial remission (PR), or document disease progression after a recent treatment regimen. At least 1, but less than 5, prior treatment regimens for MCL (Note: subjects who received previous treatment with bortezomib in a cycle of 2, either as part of a single drug or combination treatment regimen. Is considered to be exposed to bortezomib). You are willing to participate in all required assessments and procedures in this research protocol, including effortlessly swallowing capsules. Understand the purpose and dangers of the study and be able to sign and date informed consent and approval of the use of protected health information (according to national and local subject privacy rules).</p><p> Key exclusion criteria: chemotherapy within 3 weeks, nitrosurea within 6 weeks, therapeutic anti-cancer antibody within 4 weeks, radiation or toxin immune complex within 10 weeks, radiation within 3 weeks Major surgery within 2 weeks of treatment or initial administration of study drug. In the opinion of researchers, any life-threatening illness, condition, or organ system that may compromise subject safety, interfere with the absorption and metabolism of Compound 1 capsules, or place the findings at undue risk. Dysfunction. Clinically significant heart disease such as uncontrolled or symptomatic arrhythmia, congestive heart failure, or myocardial infarction within 6 months of screening, or any class as defined by the New York Heart Association functional classification. 3 or 4 heart disease. Malabsorption syndrome, diseases that significantly affect gastrointestinal function, or resection of the stomach, small intestine, or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. Any of the following laboratory abnormalities: 1. Absolute neutrophil count (ANC) &lt;750 cells / mm3 (0.75 x 109 / L) unless documented bone marrow involvement is present. 2. Platelet count &lt;50,000 cells / mm3 (50 × 109 / L) independent of fluid support, unless documented bone marrow involvement exists. 3. Serum aspartate transaminase (AST / serum GOT) or alanine transaminase (ALT / serum GPT)&gt; 3.0 x histological upper limit of normal (ULN). 4. Creatinine&gt; 2.0 x ULN.</p><p>&lt;Example 14: Phase 2 study of compound 1 plus rituximab in patients with high-risk chronic lymphocytic leukemia and small lymphocytic lymphoma&gt; Objective: The goal of this clinical study is to combine compound 1 with rituximab. One is to know if it can help control chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The safety of this combination is also studied.</p><p> Rituximab (375 mg / m) given intravenously (IV) on days 1, 8, 15, and 22²) Was then continued once every 4 weeks, only on the first day between cycles 2-6. Compound 1 is started orally daily at a dose of 420 mg (3 x 140 mg capsules) on the second day of cycle 1 and continues daily.</p><p> First endpoint: progression-free survival (PFS) [timeframe: 3 months]-Advance-free survival, defined as the time interval between treatment and early-onset progressive disease or death. Patients with complete remission (CR), partial remission (PR), or stable disease (SD) are all counted as non-progressive. Survival or time for progressive function assessed using the Kaplan-Meier method.</p><p> Second endpoint: toxicity [timeframe: 3 months]-Toxicity reported by type, frequency, and severity. The worst toxicity grades for each patient were tabulated for selected adverse events and laboratory measurements. Toxicity (grade 3 or 4) was monitored based on the Bayesian model (beta-binomial), assuming an innate possibility of toxicity after beta (1,1).</p><p> Eligibility: 18+; both genders are eligible.</p><p> Inclusion Criteria: 1. Patients must have a diagnosis of high-risk CLL / SLL and must be previously treated by up to three lines of previous treatment. High-risk CLL and high-risk SLL are defined by the presence of a 17p deletion or an 11q deletion or a mutation in TP53. Patients with any CLL and SLL with a short duration of remission less than 3 years after previous first-line immunochemotherapy, such as the FCR regimen, are also at high risk for CLL / with or without cytogenetic abnormalities. Meet SLL standards. Patients with CLL and SLL with a 2.17p deletion or mutation in TP53 may receive any previous treatment given the poor results of patients with CLL / SLL against standard first-line immunochemotherapy. Not required to receive, such patients are eligible if they have not been treated or have received up to three lines of previous treatment. 3. Patient 2008 Must have indicators of treatment according to IWCLL standards. 4. Patients&gt; 18 years old at the time of signing informed consent. Understand informed consent and voluntarily sign. Study procedures and follow-up studies can be followed. 5.0-1 ECOG / WHO performance status. 6. Patients of childbearing potential have very effective fertility control (eg, condoms, implants, injections, combined oral contraceptives) during the study and for 30 days after the last dose of the study drug. , Some intrauterine devices [IUD], sexual abstinence, or partner sterilization) must be performed comfortably. Women of childbearing potential include any woman who has experienced a first menopause and has not undergone successful sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or has not been postmenopausal. Postmenopausal is defined as: amenorrhea&gt; / = 12 consecutive months without another cause, and documented serum follicle-stimulating hormone (FSH) levels&gt; 35 mIU / mL; possible childbirth Men are any men who have not been surgically sterilized. 7. Appropriate renal and hepatic function as indicated by any of the following: Total bilirubin &lt;/ = 1.5 x systematic normal, except for patients with elevated bilirubin due to Gilbert's disease who are found to be involved Upper limit (ULN); ALT &lt;/ = 2.5 × ULN; and an assessed creatinine clearance (CrCl) of&gt; 30 mL / min, as calculated by the Cockroft-Gault equation, unless associated disease. 8. There are no previous malignancies of 3 years, except for currently treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the neck or breast. 9. A urine pregnancy test (within 7 days of day 1) is required for women of childbearing potential.</p><p> Exclusion criteria: 1. Women who are pregnant or breastfeed. 2. Chemotherapy, immunochemotherapy, monoclonal antibody therapy, radiation therapy, high-dose corticosteroid therapy (daily, more than 60 mg of prednisone or equivalent), within 21 days prior to enrollment or cooperation in this experiment. Or treatments that include immunotherapy. 3. An investigational drug that has been received within 30 days prior to the first dose of the study drug or has previously ingested Compound 1. If any study drug is received prior to this point, drug-related toxicity must be restored to grade 1 or lower prior to the first dose of study drug. 4. Uncontrolled, systemic fungi, bacteria, viruses, or other infections (showing ongoing signs / symptoms associated with the infection and without improvement despite appropriate antibiotics or other treatments) Is defined as). 5. Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune thrombocytopenia (ITP). 6. Patients with severe hematopoietic insufficiency as defined by absolute neutrophil counts &lt;500 / micro-L and / or platelet counts &lt;30,000 / micro-L at the time of screening for this protocol. .. 7. Severe organ dysfunction of the heart, kidneys, liver, or other organ system that puts the patient at excessive risk for any other severe complications or treatment with Compound 1 and rituximab Or have a history of the disease. 8. Significant heart disease such as uncontrolled or symptomatic arrhythmia, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 as defined by the New York Heart Association functional classification. Or 4 heart diseases. 9. Significant screening ECG abnormalities, including left bundle branch block, second degree AV block type II, third degree block, bradycardia, and QTc&gt; 470 msec. 10. Any severe medical condition, laboratory anomaly, or psychosis that puts the subject at unacceptable risk if the subject is involved in the study. History of stroke or cerebral hemorrhage within 11.6 months. 12. Evidence of bleeding diathesis or abnormal blood clots. 13. Predictions required for major surgical procedures within 28 days prior to the first day, direct biopsy, or significant trauma, major surgical procedures during the course of the study. 14. Small 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, unhealed wounds, ulcers, or fractures. 16. Treatment with Coumadin. Patients who have recently received Coumadin should stop Coumadin for at least 7 days before the study begins. 17. Any chemotherapy (eg, bendamstin, cyclophosphamide, pentostatin, or fludalabine), immunotherapy (eg, alemtuzumab, or ofatumumab), bone marrow transplantation, experimental treatment, or radiation therapy are included in this study. Banned during treatment. 18. Drug use, known to extend the QTc interval or may be associated with Torsades de Pointe (referring to Annex F), is prohibited within 7 days of study drug initiation and during study drug treatment. Will be done.</p><p> The examples and embodiments described herein are exemplary and various modifications or modifications suggested to those of skill in the art should be included within this disclosure. As will be appreciated by those skilled in the art, certain components listed in the above examples may be replaced with other functionally equivalent components such as excipients, binders, lubricants, fillers and the like.</p>