Crystalline forms of a bruton's tyrosine kinase inhibitor.

(54) Title: CRYSTALLINE FORMS OF A BRUTON TYROSINE KINASE INHIBITOR.

(54) Title: CRYSTALLINE FORMS OF A BRUTON'S TYROSINE KINASE INHIBITOR.

(57) Summary

The present invention relates to Bruton's tyrosine kinase (Btk) inhibitor 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine -1-yl) piperidin-1-yl) prop-2-en-1-one, including crystalline forms, solvates and their pharmaceutically acceptable salts. Pharmaceutical compositions including the Btk inhibitor are also described, as well as methods for using said inhibitor alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, as well as diseases. or inflammatory conditions.

(57) Abstract

Described herein is the Bruton's tyrosine kinase (Btk) inhibitor 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1 H-pyrazolo [3,4d] pyrimid ¡n-1-yl) piperid¡n-1-yl) prop-2-en-1-one, including crystalline forms, solvates and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions that inelude the Btk inhibitor, as well as methods of using the Btk inhibitor, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

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PATENT TITLE No. 348290

Owner (s): PHARMACYCLICS LLC

Address: 995 East Arques Avenue, Sunnyvale, California, 94085, USA

Denomination: CRYSTALLINE FORMS OF A BRUTON TYROSINE KINASE INHIBITOR.

Classification: CIP: C07D487 / 04; A61K9 / 48; A61K47 / 30; A61K47 / 38; A61P29 / 00; A61P35 / 00

CPC: C07D487 / 04; A61K9 / 2013; A61K9 / 2018: A61K9 / 2054; A61K9 / 4858;

A61K9 / 4866; A61K31 / 519; A61K45 / 06,

CSetl: A61K2300 / 00; A61K31 / 519

Inventor (s): MARK SMYTH; ERICK GOLDMAN; DAVID D. WIRTH; NORBERT PURRO

REQUEST

<td>Number:</td><td>International Presentation Date:</td>

<td>MX / a / 2014/014848</td><td>June 03, 2013</td>

PRIORITY

Country: Date: Number:

US June 4, 2012 61 / 655,381

Validity: Twenty years

Expiration Date: June 3, 2033

Issue Date: June 5, 2017

The reference patent is granted based on articles 1^or, 2^orSection V, 8th Section III, and 59 of the Industrial Property Law.

In accordance with article) 23 of the Industrial Property Law, this patent is valid for twenty years, renewable, counted from the date of filing the application and will be subject to the payment of the fee to keep the rights in force.

Whoever subscribes to this title does so based on the provisions of articles 6 "fractions lll and 7 ° tus 2 of the Industrial Property Law (Official Gazette of the Federation (O.OF.) 06/27/1991, amended on Q2 / 08/1994, 10/26/1996, 12/26/1997, 05/17/1999, 01/26/2004, 06/16/2005, 01/25/2006, 05/06/2009,06 / 01/2010, 06/18/2010, 06/28/2010, 01/27/2012 and 04/09/2012); Articles 1, 3 »fraction V subsection a), 4» and 12^or Sections I and III of the Regulations of the Mexican Institute of Industrial Property (DOF 12/14/1999, amended on 07/01/2002, 07/15/2004, 07/28/2004 and 09/07/2007); items 1^or, 3^or, 4^or, 5^or Section V subsection a), 16 sections I and III and 30 of the Organic Statute of the Mexican Institute of Industrial Property (DOF 12/27/1999, amended on 10/10/2002, 07/29/2004, 08/04/2004 and 09/13/2007); one^or, 3^or and 5 ° 9icisoa) of the Agreement that delegates powers to the Deputy General Directors, Coordinator, Directors' DMsfonal, Titü1aree de alas ,. Regional Oftanás, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Mexican Institute of Industrial Property. (DOF 12/15/1999, amended on 02/04/2000, 07/29/2004, 08/04/2004 and 09/13/2007).

This document is signed with an advanced electronic signature (FIEL), based on articles 7 BIS 2 of the Industrial Property Law; 3 of its Regulations, and 1 fraction lll, 2 fraction V, 26 BIS and 26 TER of the Agreement establishing the guidelines for the use of the Payment and Electronic Services Portal (PASE) of the Mexican Institute of Industrial Property, in the procedures indicated.

THE DIVISIONAL DIRECTOR OF PATENTS

<img file="MX348290B_D0001.tif" />

NAHANNY CANAL REYES

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INSTITUTO MLXICANi of the amount *

CRYSTAL FORMS OF A QUlKMSg'TSE TYROSINE INHIBITOR

BRUTON

The present application claims the benefit of US Provisional Patent Application No. 61 / 655,381 entitled CRYSTALLINE FORMS OF A BRUTON TYROSINE KINASE INHIBITOR filed on June 4, 2012, which is hereby incorporated in its entirety by reference.

FIELD OF THE INVENTION

The Bruton tyrosine kinase inhibitor is described herein. (Btk) l - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -ΙΗ-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-1ill) prop-2-en-l -one, including its crystalline forms, solvates and pharmaceutically acceptable salts, as well as pharmaceutical compositions including the Btk inhibitor and methods of using the Btk inhibitor in the treatment of diseases or disorders that would benefit from the inhibition of Btk activity .

BACKGROUND OF THE INVENTION

Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all types of hematopoietic cells except T lymphocytes and cells.

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INSTITUTO MEXICAN · 'DE LA WHíDM) INOCSTHIAL natural killer cells. Btk plays an essential role in the B cell signaling pathway linking stimulation of the cell surface B cell receptor (BCR) with downstream intracellular responses.

Btk is a key regulator in B cell development, activation, signaling, and survival. Additionally, Btk plays a role in a number of other hematopoietic cell signaling pathways, eg, the Toll-like receptor (TLR) and macrophage receptor-mediated TNF-Ü cytokine production, receptor signaling. IgE (FcepsilonRI) in mast cells, inhibition of apoptotic Fas / APO-1 signaling in B lineage lymphoid cells, and collagen-stimulated platelet clumping.

1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4d] pyrimidin-l-ill) piperidin-l-ill) prop-2-en-l- one is also known by its IUPAC name as 1 - {(3R) -3- [4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-ill] piperidin-1ill} prop -2-en-l-one or 2-Propen-l-one, 1 - [(3R) -3- [4-amino-3 (4-phenoxyphenyl) -lFf-pyrazolo [3,4-d] pyrimidin- l-ill] -1piperidinyl- and has received the USAN name, ibrutinib. The various names given to ibrutinib are used interchangeably herein.

SUMMARY OF THE INVENTION

MEXICAN INSTITUTE

Described herein is the inhibition of A? BS5 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4 ......

d] pyrimidin-l-ill) piperidin-l-ill) prop-2-en-l-one, including pharmaceutically acceptable solvates (including hydrates), polymorphous and amorphous phases and methods of use thereof. Pharmaceutically acceptable salts of the Btk inhibitor are also described, including pharmaceutically acceptable solvates (including hydrates), polymorphous and amorphous phases, and methods of use thereof. 1 - ((R) -3- (4-Amino3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-lill) piperidin-l-ill) prop-2-en-l-one, as well as their pharmaceutically acceptable salts, they are used in the manufacture of medicaments for the treatment of diseases or disorders related to the activity of Btk. 1 - ((R) -3- (4-Amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-lill) prop-2-en-l-one is an irreversible inhibitor of Btk.

Also described herein are methods of preparing the crystalline forms of 1 - ((R) -3- (4-amino-3 (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l- ill) piperidinl-ill) prop-2-en-l-one. Further described are pharmaceutical compositions that include crystalline forms and methods of using the Btk inhibitor in the treatment of diseases or disorders (including diseases or disorders where irreversible inhibition of Btk "IMPTíss" provides therapeutic benefits to a peanut disease or disorder). In one embodiment it is l - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-lill) prop-2-en -l-one anhydrous.

In another embodiment it is l - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-1ill) prop-2-en- anhydrous crystalline l-one.

In a further embodiment is 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-1-ill) piperidin-lill) prop-2-en -Anhydrous amorphous l-one.

In one aspect it is a 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-lill) prop-2 solvate -en-l-one.

In one embodiment it is a solvate, where 1- ((R) -3- (4 amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-lill) piperidin-l-ill) prop- 2-en-l-one is solvated with methyl isobutyl ketone (MIBK), toluene, or methanol. In u embodiment it is a solvate, where 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-lill) prop -2-en-l-one is solvated with methyl isobutyl ketone (MIBK) or toluene. In one embodiment it is a solvate, where 1 ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4d] pyrimidin-l-ill) piperidin-l-ill) prop -2-en-l-one se

<img file="MX348290B_D0003.tif" />

found 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 aspect, a

1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop-2- Form A on-canvas that has at least one of the following properties:

(a) an X-ray diffraction pattern (XRPD) 10 substantially the same as that shown in Fig. 1;

(b) an X-ray diffraction pattern (XRPD) with characteristic peaks at 5,710.1 ° 2-Theta, 13,610.1 ° 2-Theta, 16,110.1 ° 2-Theta, 18.9 + 0.1 ° 2 -Theta, 21.3 + 0.1 ° 2-Theta, and 21.610.1 ° 2-Theta;

(c) substantially the same X-ray diffraction pattern (XRPD) after storage at 40 ° C and 75% RH for at least one week;

(d) substantially the same X-ray diffraction pattern (XRPD) after storage at 25 ° C and 97% RH for at least one week;

(e) Infrared (IR) spectrum substantially similar to that set forth in Fig. 2;

(f) Weak peaks in the infrared (IR) spectrum at approximately 1584 cm '¹, about 1240 cm^-1,

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INSTITUTO MiXICAN '_r> about 1147 cm '¹, about 1099 cm '¹ and approximately 1067cm ~ r ~ —-—----- (g) A DSC thermogram substantially similar to that set forth in Fig. 3;

(h) A thermogravimetric analysis (TGA) thermogram substantially similar to that set forth in Fig. 4;

(i) A DSC thermogram with an endotherm having a start at about 154 ° C and a peak at about 157 ° C and an exotherm at about 159 ° C;

(j) non-hygroscopicity;

(k) an observed aqueous solubility of about 0.013 mg / mL at about pH 8;

or (1) their combinations.

In some embodiments, crystalline Form A has an X-ray diffraction pattern (XRPD) substantially the same as that shown in Fig. 1. In some embodiments, crystalline Form A has a peaked X-ray diffraction pattern (XRPD). characteristic at 5.7 ± 0, l ° 2-Theta, 13.6 ± 0, l ° 220 Theta, 16, l ± 0, l ° 2-Theta, 18.9 ± 0, l ° 2-Theta, 21 , 3 ± 0, l ° 2-Theta and 21.6 ± 0, l ° 2-Theta. In some embodiments, the crystalline Form A has substantially the same X-ray diffraction pattern (XRPD) upon storage at 40 ° C and 75% RH for at least one week. In some

ΙΝΪΤΓΓΙΓΤΟ MEXICANO M LA rWHEDAO INDUSTRIAL

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INSTm ΓΓιλ umriN ,, embodiments, the crystalline Form A has substantially the same X-ray diffraction pattern (XRPD) upon storage at 25 ° C and 97% RH for at least one week. In some embodiments, crystalline Form A has an infrared (IR) spectrum substantially similar to that set forth in Fig. 2. In some embodiments, crystalline Form A has weak infrared (IR) spectrum peaks at about 1584 cm '¹, about 1240 cm^-1, about 1147 cm^-1, approximately 1134 cm^-1, about 1099 cm^-1 and about 1067cm^-1. In some embodiments, crystalline Form A has a melting temperature of about 155-156 ° C. In some embodiments, crystalline Form A has a DSC thermogram substantially similar to that set forth in Fig. 3. In some embodiments, crystalline Form A has a thermogravimetric analysis thermogram (TGA) substantially similar to that set forth in Fig. 4. In some embodiments, the crystalline Form A has a DSC Thermogram with an endotherm that has a beginning at about 154 ° C and a peak at about 157 ° C and an exotherm at about 159 ° C. In some embodiments, the crystalline Form A is non-hygroscopic. In some embodiments, the crystalline Form A has an observed aqueous solubility of about 0.013 mg / mL at about pH 8. In some

IMPI tMSTTTUTO MEXICANO OE LA PRONSDAD realizations, the FÓÍWá

<img file="MX348290B_D0004.tif" />

crystalline that is characterized by having properties [aT, (b) T (c), (d), (e), (f), (g), (h), (i), (j) and (k). In some embodiments, the crystalline Form A was obtained from ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE). ), anisole, acetone, heptanes, a methanol / water mixture or an acetone / heptane mixture. In some embodiments, the Shape

A crystalline was obtained from a methanol / water mixture. In some embodiments, the crystalline Form A is not solvated.

In some embodiments, the crystalline Form A is anhydrous.

In one aspect, a

Form B crystalline 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H15 pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop-2 -on-canvas that has at least one of the following properties:

(a) an X-ray diffraction pattern (XRPD) substantially the same as that shown in Fig. 5;

(b) an X-ray diffraction pattern (XRPD) with characteristic peaks at 5.2 ± 0.1 ° 2-Theta, 10.2 ± 0.1 ° 2-Theta, 16.5 ± 0.1 ° 2 -Theta, 18.5 ± 0.1 ° 2-Theta and 20.8 + 0.1 ° 2-Theta;

(c) substantially the same X-ray diffraction pattern (XRPD) after storage at 40 ° C and 75% RH for at least one week;

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OF THE HüPlBUA?

INDUSTWAL (d) substantially the same diffraction pattern of. X-ray (XRPD) after storage at 25 ° C and 97% RH for at least one week;

(e) Infrared (IR) spectrum substantially similar to that set forth in Fig. 6;

(f) Weak peaks in the infrared (IR) spectrum at approximately 1586 cm '¹, about 1573cm about 1562 cm^-1, about 1229cm about 1141cm^-1, about 1103cm about 1056 cm^-1 and approximately 1033 cm '¹;

(g) a DSC thermogram substantially similar to that set forth in Fig. 7;

(h) a thermogravimetric analysis (TGA) thermogram substantially similar to that set forth in Fig. 8;

(i) a DSC thermogram with an endotherm having a beginning at about 99-106 ° C and a peak at about 115-118 ° C;

(j) an observed aqueous solubility of about 0.0096 mg / mL at a pH of about 7.42;

Or (k) their combinations.

In some embodiments, crystalline Form B has an X-ray diffraction pattern (XRPD) substantially the same as shown in Fig. 5. In some embodiments, Form '

<img file="MX348290B_D0005.tif" />

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Crystalline B has a FWPDT ray diffraction pattern with characteristic peaks at 5.2 ± 0.1 ° 2-Theta, lo, 2 ± u, i 'Theta, 16.5 ± 0.1 ° 2-Theta, 18, 5 ± 0.1 ° 2-Theta, and 20.8 + 0.1 ° 2Theta. In some embodiments, crystalline Form B has substantially the same X-ray diffraction pattern (XRPD) upon storage at 40 ° C and 75% RH for at least one week. In some embodiments, crystalline Form B has substantially the same X-ray diffraction pattern (XRPD) upon storage at 25 ° C and 97% RH for at least one week. In some embodiments, crystalline Form B has an infrared (IR) spectrum substantially similar to that set forth in Fig. 6. In some embodiments, crystalline Form B has weak infrared (IR) spectrum peaks at about 1586 cm '¹, approximately 1573 cm '¹, approximately 1562 cm '¹, approximately 1229 cm "¹, approximately 1141 cm "¹, approximately 1103 cm "¹, about 1056 cm '¹ and approximately 1033 cm '¹. In some embodiments, crystalline Form B has a DSC thermogram substantially similar to that set forth in Fig. 7. In some embodiments, crystalline Form B has a thermogravimetric analysis thermogram (TGA) substantially similar to that set forth in Fig. 8. In In some embodiments, the crystalline Form B has an IMPIg iwrmrro MyxicAN.

Ot THE PROPERTY O »DSC thermogram with an endotherm having a beginning at approximately 99-106 ° C and a peak at approximately 115-lithium ° C. In some embodiments, crystalline Form B has an observed aqueous solubility of about 0.0096 mg / mL at a pH of about 7.42. In some embodiments, crystalline Form B is characterized as having the properties (a), (b), (c), (d), (e), (f), (g), (h), (i), and (j). In some embodiments, crystalline Form B was made from a mixture of methanol and water. In some embodiments, the

Crystalline Form B is not solvated. In some embodiments, the crystalline Form B is anhydrous.

In one aspect, a

Crystalline Form C of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop-2- en-l-one that has at least one of the following properties:

(a) an X-ray diffraction pattern (XRPD) substantially the same as that shown in Fig. 9;

(b) an X-ray diffraction pattern (XRPD) with characteristic peaks at 7.0 + 0.1 ° 2-Theta, 14.0 ± 0.1 ° 2-Theta,

15.7 ± 0, l ° 2-Theta, 18.2 ± 0, l ° 2-Theta, 19, l ± 0, l ° 2-Theta,

19.5 ± 0.1 ° 2-Theta, 20.3 ± 0, l ° 2-Theta, 22.1 + 0.1 ° 2-Theta and 22.9 ± 0.1 ° 2-Theta;

(c) a DSC Thermogram substantially similar to that set forth in Fig. 10;

IMPI

INSTITUTO MEJIICAN¹ 'industrial (d) a thermogravimetric analysis (TGA) thermogram substantially similar to that set forth in Fig T11;

(e) a DSC Thermogram with an endotherm having a beginning at about 134-135 ° C and a peak at about 137-139 ° C;

or (f) their combinations.

In some embodiments, crystalline Form C has an X-ray diffraction pattern (XRPD) substantially the same as shown in Fig. 9. In some embodiments, crystalline Form C has an X-ray diffraction pattern (XRPD) with characteristic peaks. at 7.0 ± 0.1 ° 2-Theta, 14.0 + 0.1 ° 2-Theta, 15.7 + 0.1 ° 2-Theta, 18.210.1 ° 2-Theta, 19, l ± 0.1 2Theta, 19.5 ± 0, l ° 2-Theta, 20.3 ± 0, l ° 2-Theta, 22, l ± 0, l ° 2Theta and 22.9 ± 0, l ° 2-Theta. In some embodiments, crystalline Form C has a DSC Thermogram substantially similar to that set forth in Fig. 10. In some embodiments, crystalline Form C has a thermogravimetric analysis thermogram (TGA) substantially similar to that set forth in Fig. 11. In In some embodiments, crystalline Form C has a DSC Thermogram with an endotherm that has a beginning at about 134-135 ° C and a peak at about 137-139 ° C. In some embodiments, the

Form C crystalline is characterized by having properties (a),

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INSTITUTO MEXICANA> D »INDUSTRIAL PROPERTY (b), (c), (d) and (e). In some embodiments, crystalline Form C was obtained from a mixture of methanol and water. In some embodiments, the crystalline Form C is not solvated. In some embodiments, the crystalline Form C is anhydrous.

In one aspect, a

Crystalline Form D of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop-2- on-canvas that has at least one of the following properties:

(a) an X-ray diffraction pattern (XRPD) 10 substantially the same as that shown in Fig. 12;

(b) an X-ray diffraction pattern (XRPD) with characteristic peaks at 7.2 + 0.1 ° 2-Theta, 8.010.1 ° 2-Theta,

9.2 + 0.1 ° 2-Theta, 14.5 + 0.1 ° 2-Theta, 18.5 + 0.1 ° 2-Theta,

19,510.1 ° 2-Theta, 20,710.1 ° 2-Theta, 21.0 + 0.1 ° 2-Theta,

21.9 + 0.1 ° 2-Theta and 22.4 + 0.1 ° 2-Theta;

(c) a thermogravimetric analysis (TGA) thermogram substantially similar to that set forth in Fig. 13;

(d) their combinations.

In some embodiments, crystalline Form D has an X-ray diffraction pattern (XRPD) substantially the same as shown in Fig. 12. In some embodiments, crystalline Form D has an X-ray diffraction pattern (XRPD) with characteristic peaks. at 7,210.1 ° 2-Theta, 8,010.1 ° 2_1Λ IMPIAS

ΙΝΤΤΓΠΠΌ MRXICAHO

Df THE INDUSTUAL NUFIETY ^ U.

Theta, 9.2 + 0.1 ° 2-Theta, 14.5 ± 0, l ° 2-Theta, 18.5 ± 0, l ° 2-Theta, 19.5 ± 0, l ° 2-Theta, 20, 7 + 0.1 ° 2-Theta, 21 ', 0 + 0Λ ° “Theta, 21.9 ± 0, l ° 2-Theta, and 22.4 ± 0.1 ° 2-Theta. In some embodiments, the crystalline Form D has a thermogravimetric analysis (TGA) thermogram substantially similar to that set forth in Fig. 13. In some embodiments, the crystalline Form D is characterized as having the properties (a), (b), and ( c). In some embodiments, crystalline Form D was obtained from methyl isobutyl ketone (MIBK). In some embodiments, the crystalline Form D is solvated. In some embodiments, the crystalline Form D is solvated with methyl isobutyl ketone (MIBK).

In one aspect, a crystalline Form E of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-ill) is described herein. ) piperidin-l-ill) prop-2-in-canvas having at least one of the following properties:

(a) an X-ray diffraction pattern (XRPD) substantially the same as that shown in Fig. 14;

(b) an X-ray diffraction pattern (XRPD) with characteristic peaks at 7.8 ± 0.1 ° 2-Theta, 8.8 ± 0.1 ° 2-Theta, 16.1 ± 0.1 ° 2 -Theta, 18.1 + 0.1 ° 2-Theta, 19.3 ± 0, l ° 2-Theta, 19.5 + 0.1 ° 2-Theta, 20.5 ± 0, l ° 2-Theta , 21.6 ± 0.1 ° 2-Theta and 25.2 ± 0.1 ° 2-Theta;

(c) a DSC Thermogram substantially similar to the

<img file="MX348290B_D0006.tif" />

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INDUST1UAL established in Fig. 15;

(d) a thermogravimetric analysis (TGA) thermogram substantially similar to that set forth in Fig. 15;

(e) their combinations.

In some embodiments, crystalline Form E has an X-ray diffraction pattern (XRPD) substantially the same as shown in Fig. 14. In some embodiments, crystalline Form E has an X-ray diffraction pattern (XRPD) with characteristic peaks. at 7.8 ± 0, l ° 2-Theta, 8.8 ± 0, l ° 2-Theta, 16, l ± 0, l ° 2-Theta, 18.1 + 0.1 ° 2-Theta, 19.3 ± 0.1 ° 2-Theta, 19.5 + 0.1 ° 2-Theta, 20.5 + 0.1 ° 2-Theta, 21.6 ± 0, l ° 2Theta, and 25.2 ± 0.1 ° 2-Theta. In some embodiments, the

Form E crystalline has a DSC Thermogram substantially similar to that set forth in Fig. 15. In some embodiments, Form E crystalline has a thermogravimetric analysis (TGA) thermogram substantially similar to that set forth in FIG. 15. In some embodiments, Form E crystalline is characterized by having the properties (a), (b), (c) and (d). In some embodiments, the crystalline Form E was obtained from toluene. In some embodiments, the crystalline Form E is solvated. In some embodiments, the crystalline Form E is solvated with toluene.

In one aspect, a ₁₆ ΙΜΡΙ $ ustttuto m &amp; xicamo

M LA HtORfOA · Qt Form F crystalline 1- ((R) -3- (4-amino-3- (i-phenoxypheHMT ^ lH ^ pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l- ill) -Sfi-l¹one that has at least one of the following properties:

(a) an X-ray diffraction pattern (XRPD) substantially the same as that shown in Fig. 16;

(b) an X-ray diffraction pattern (XRPD) with characteristic peaks at 6.2 ± 0.1 ° 2-Theta, 10, l ± 0.1 ° 2-Theta, 17.6 ± 0.1 ° 2 -Theta, 18.6 + 0.1 ° 2-Theta, 20.0 ± 0, l ° 2-Theta,

20.4 + 0.1 ° 2-Theta, 20.7 ± 0, l ° 2-Theta, 22.4 ± 0, l ° 2-Theta,

23.0 ± 0.1 ° 2-Theta, 23.2 + 0.1 ° 2-Theta, 24.4 ± 0, l ° 2-Theta,

25, l ± 0, l ° 2-Theta, 27.6 + 0.1 ° 2-Theta, 29.3 + 0.1 ° 2-Theta, and 29.7 ± 0, l ° 2-Theta;

(c) unit cell parameters substantially equivalent to the following at 100 (2) K:

<img file="MX348290B_D0007.tif" />

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INSTITUTO MIXICAN i 0 «LA TROAIEDAD industrial

<td>System of crystals</td><td colspan="5">Triclinic</td>

<td rowspan="3">Space group</td><td rowspan="3">P1</td><td>to</td><td>9.6332 (3) Á</td><td> □</td><td> 105, 762 (3)°</td>

<td>b</td><td>9.7536 (4) Á</td><td> □</td><td> 95,132 (2)⁰</td>

<td>c</td><td>15.0592 (4) TO</td><td> □</td><td> 111, 332 (3)⁰</td>

<td>V</td><td colspan="5">1240.15 (7) Á³</td>

<td>Z</td><td colspan="5"> 1</td>

<td>Density (calculated)</td><td colspan="5">1.308 Mg / m³</td>

<td>Absorption coefficient</td><td colspan="5">0.726 mm '¹</td>

<td>Lenght of wave</td><td colspan="5">1.54178 Á</td>

<td>F (000)</td><td colspan="5"> 518</td>

or (d) their combinations.

In some embodiments, the crystalline Form F has an X-ray diffraction pattern (XRPD) substantially the same as that shown in Fig. 16. In some embodiments, the crystalline Form F has an X-ray diffraction pattern (XRPD) with characteristic peaks at 6.2 + 0.1 ° 2-Theta, 10,110.1 ° 2Theta, 17,610.1 ° 2-Theta, 18 .6 + 0.1 ° 2-Theta, 20.0 ± 0, l ° 2-Theta, 20.4 + 0.1 ° 2-Theta, 20.7 + 0.1 ° 2-Theta, 22.4 + 0 , 1 ° 2-Theta, 23.010.1 ° 2-Theta, 23.2 ± 0, l ° 2-Theta, 24.410.1 ° 2Theta, 25.110.1 ° 2-Theta, 27.6 + 0.1 ° 2-Theta , 29.3 + 0.1 ° 2-Theta and 29.7 + 0.1 ° 2-Theta.

<img file="MX348290B_D0008.tif" />

IMPI «aiCANo 04 THE INDUSTRY MOTIVATION!

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

<td>System of crystals</td><td colspan="5">Triclinica</td>

<td rowspan="3">Space group</td><td rowspan="3">P1</td><td>to</td><td>9.6332 (3) A</td><td> □</td><td> 105,762(3)°</td>

<td>b</td><td>9.7536 (4) Á</td><td> □</td><td> 95, 132 (2) ⁰</td>

<td>c</td><td>15.0592 (4) A</td><td> □</td><td> 111,332 (3)°</td>

<td>V</td><td colspan="5">1240.15 (7) A³</td>

<td>Z</td><td colspan="5"> 1</td>

<td>Density (calculated)</td><td colspan="5">1.308 Mg / m³</td>

<td>Absorption coefficient</td><td colspan="5">0.726 mm^-1</td>

<td>Lenght of wave</td><td colspan="5">1.54178 A</td>

<td>F (000)</td><td colspan="5"> 518</td>

In some embodiments, the crystalline Form F was obtained from methane !.

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

In one aspect, described herein is a pharmaceutically acceptable salt of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -iH-pyrazolo [3,4-d] pyrimidin-l-ill ) piperidin-1ill) prop-2-en-l-one, where the pharmaceutically acceptable salt

<img file="MX348290B_D0009.tif" />

IMPI

INSTITUTO DE LA is an acid addition salt. In some realizations^N8nes, pharmaceutically acceptable salt is amorphous .--- In some embodiments, the pharmaceutically acceptable salt is crystalline.

In a further aspect pharmaceutical compositions are provided, which include l - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin- lill) prop-2-en-l-one as described herein and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients. In some embodiments, the pharmaceutical composition comprises Form A. In some embodiments, the pharmaceutical composition comprises Form B. In some embodiments, the pharmaceutical composition comprises Form C. In some embodiments, the pharmaceutical composition comprises Form D. In some embodiments, the pharmaceutical composition comprises Form E. In some embodiments In embodiments, the pharmaceutical composition comprises Form F. In some embodiments, the pharmaceutical composition is in a form suitable for administration to a mammal. In some embodiments, the pharmaceutical composition is in an oral solid dosage form. In some embodiments, the pharmaceutical composition comprises about 0.5mg to about 100mg of 1 ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4d] pyrimidin-l-ill ) piperidin-l-ill) prop-2-en-1-one crystalline.

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

(a) about 40 mgs to about 200 mgs of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4d] pyrimidin-l-ill) piperidin-l -ill) prop-2-en-1-one;

(b) about 40% by weight to about

fifty % by weight of a diluent;

(c) about 3% by weight to about% by weight of a disintegrating agent;

(d) about 2% by weight to about 7% by weight of a surfactant; and (e) about 0.2% by weight to about

1.0% by weight of a lubricant.

In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talcum powder. In some embodiments the diluent is microcrystalline cellulose. In some embodiments, the disintegrating agent is selected from the group consisting of

<img file="MX348290B_D0010.tif" />

IMPI in natural starch (MSTITUTO MLXlCANv, M LA MOHEDA »a pregelatinized starch, a sodium alWiW'h, methylcrystalline cellulose, iiic Li 1 tu Id luya?

croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, clay or a sodium alginate, a sodium clay or a sodium alginate. In some embodiments, the disintegrating agent is croscarmellose sodium. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, ethylene oxide and propylene oxide 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, cornstarch, sodium stearyl fumerate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, a pharmaceutical formulation for administration is provided herein

IMPI '^' WIOMUICAMU ^ÜlLA, oral indostmal which includes:

(a) about 40 mgs to about 200 mgs of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4d] pyrimidin-l-ill) piperidin-l -ill) prop-2-en-l-one;

(b) about 40% by weight to about 50% by weight microcrystalline cellulose;

(c) about 3% by weight to about 10% by weight croscarmellose sodium;

(d) about 2% by weight to about 7% by weight of sodium lauryl sulfate; and (e) about 0.2% by weight to about 1.0% by weight of magnesium stearate.

In some embodiments, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) about 40% by weight to about 50% by weight of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l -ill) piperidin-l-ill) prop-2-en-l-

<img file="MX348290B_D0011.tif" />

one; '(b) about 40% by weight to about 50% by weight microcrystalline cellulose;

(c) about 3% by weight to about 10% by weight croscarmellose sodium;

(d) about 2% by weight to about 7

<img file="MX348290B_D0012.tif" />

% by weight sodium lauryl sulfate; Y

IMPI or industrial mohedal (e) about 0.2% by weight to about 1.0% by weight of magnesium stearate.

In some embodiments, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) 140 mgs of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop-2-on-canvas;

(b) 45.9% by weight microcrystalline cellulose;

(c) 7.0% by weight croscarmellose sodium;

(d) 4.2% by weight of sodium lauryl sulfate; and (e) 0.5% by weight of magnesium stearate.

In some embodiments, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) 140 mgs of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop-2-on-canvas;

(b) 151.4 mgs of microcrystalline cellulose;

(c) 23.0 mgs of croscarmellose sodium;

(d) 14.0 mgs of sodium lauryl sulfate; and (e) 1.6 mgs of magnesium stearate.

In another aspect, it is provided herein

IMPI instituto mexican i a pharmaceutical formulation for administration

<img file="MX348290B_D0013.tif" />

understands:

(a) about 40 mgs to about 200 mgs of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4d] pyrimidin-l-ill) piperidin-l -ill) prop-2-en-l-one crystalline;

(b) about 40% by weight to about 50% by weight of a diluent;

(c) about 3% by weight to about 10% by weight of a disintegrating agent;

(d) about 2% by weight to about 7% by weight of a surfactant; and (e) about 0.2% by weight to about 1.0% by weight of a lubricant.

In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. . In some embodiments the diluent is microcrystalline cellulose. In some embodiments, the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, carboxymethylcellulose of

IMPI ^

5 HJTiTtrro Mexican>

M THE MOLD »c industual> cross-linked sodium, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay or a gum. In some embodiments, the disintegrating agent is croscarmellose sodium. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, ethylene oxide and propylene oxide 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, cornstarch, sodium stearyl fumerate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) about 40 mgs to about 200 mgs of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4-

IMPIfí fNSTTnrruMuicANo C

C LA PRuPIttAÍ km ^{z 0} induthiial V

crystalline d] pyrimidin-l-ill) piperidin-l-ill) prop-2-en-l-one;

(b) about 40% by weight to about 50% by weight microcrystalline cellulose;

(c) about 3% by weight to about 10% by weight croscarmellose sodium;

(d) about 2% by weight to about 7% by weight of sodium lauryl sulfate; and (e) about 0.2% by weight to about 1.0% by weight of magnesium stearate.

In some embodiments, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) about 40% by weight to about% by weight of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop-2-en-crystalline canvas;

(b) about 40% by weight to about 50% by weight microcrystalline cellulose;

(c) about 3% by weight to about 10% by weight croscarmellose sodium;

(d) about 2% by weight to about 7% by weight of sodium lauryl sulfate; and (e) about 0.2% by weight to about 1.0% by weight of magnesium stearate.

<img file="MX348290B_D0014.tif" />

In present some embodiments, a formulation was documented MPI

MtXICAN INSTITUTE

Di LA NONEDAD INDUSTRIAL provides in the pharmaceutical for oral administration which comprises:

(a) 140 mgs of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop -2-en-l one crystalline;

(b) 45.9% by weight microcrystalline cellulose;

(c) 7.0% by weight croscarmellose sodium;

(d) 4.2% by weight of sodium lauryl sulfate; and (e) 0.5% by weight of magnesium stearate.

In some embodiments, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) 140 mgs of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop-2-in-crystalline canvas;

(b) 151.4 mgs of microcrystalline cellulose;

(c) 23.0 mgs of croscarmellose sodium;

(d) 14.0 mgs of sodium lauryl sulfate; and (e) 1.6 mgs of magnesium stearate.

In some embodiments of the above pharmaceutical embodiments, l - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill ) crystalline prop-2-en-l-one is crystalline Form A. In

<img file="MX348290B_D0015.tif" />

IMPI

OF THE 'NOUSTRIAL PROPERTY some realizations of the previous pharmaceutical realizations,

1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop-2-en-crystalline canvas is Form B crystalline. In some embodiments of the above pharmaceutical embodiments, 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4d] pyrimidin-l-ill) piperidin-l-ill ) prop-2-en-l-one crystalline is Form C crystalline. In some embodiments of the above pharmaceutical embodiments, l - ((R) -3- (4-amino-3 (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-ill) piperidinl-ill) Crystalline prop-2-en-l-one is Form D crystalline. In some embodiments of the above pharmaceutical embodiments, 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill ) prop-2-in-canvas crystalline is Form E crystalline. In some embodiments of the above pharmaceutical embodiments, 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4d] pyrimidin-l-ill) piperidin-l-ill ) prop-2-en-l-one crystalline is Form F crystalline. In some embodiments of the above pharmaceutical embodiments, l - ((R) -3- (4-amino-3 (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-ill) piperidinl-ill) prop-2-en-l-one crystalline is a mixture of two or more crystalline forms selected from the group consisting of Form A, Form B, Form C, Form D, Form E, and Form F. En and wl ·। ,or .

IΜ PI • INSTITUTO MEXICANO Í ^ Cw-T-qi · J

OR q OF THE PROPERTY tX— g.

industrial W ** T - another embodiment of the above pharmaceutical embodiments provided herein, is a pharmaceutical formulation where the dosage form is a hard gelatin capsule.

In another aspect, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) about 40 mgs to about 200 mgs of Form A crystalline 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l- ill) piperidin-1 ill) prop-2-en-l-one;

(b) about 40% by weight to about 50% by weight of a diluent;

(c) about 3% by weight to about 10% by weight of a disintegrating agent;

(d) about 2% by weight to about 7% by weight of a surfactant; and (e) about 0.2% by weight to about 1.0% by weight of a lubricant.

In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrase, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. . In some it is microcrystalline cellulose. In

<img file="MX348290B_D0016.tif" />

Disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linked starch-like cross-linked croscarmellose, for example cross-linked starch sodium, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay or a rubber. In some embodiments, the disintegrating agent is croscarmellose sodium. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, ethylene oxide and propylene oxide 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, cornstarch, sodium stearyl fumerate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes.

In some embodiments, the lubricant is stearate

<img file="MX348290B_D0017.tif" />

<img file="MX348290B_D0018.tif" />

NSTmrro_MEXICAthe MOH ^ ao 'noustriai magnesium.

In some embodiments, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) about 40 mgs to about 200 mgs of Form A crystalline 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-l- ill) piperidin-1ill) prop-2-en-l-one;

(b) about 40% by weight to about 50% by weight microcrystalline cellulose;

(c) about 3% by weight to about 10% by weight croscarmellose sodium;

(d) about 2% by weight to about 7% by weight of sodium lauryl sulfate; and (e) about 0.2% by weight to about 1.0% by weight of magnesium stearate.

In some embodiments, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) about 40% by weight to about 50% by weight of crystalline Form A of l - ((R) -3- (4-amino-3 (4-phenoxyphenyl) -IH-pyrazolo [3,4-d ] pyrimidin-l-ill) piperidin-1-ill) prop-2-en-l-one;

(b) about 40% by weight to about

<img file="MX348290B_D0019.tif" />

IMPI

UTO MÍXICan,, DI LA HROFüDAD 'NUMMAL% by weight of microcrystalline cellulose; ___ (c) about 3% by weight to about% by weight croscarmellose sodium;

(d) about 2% by weight to about 7% by weight of sodium lauryl sulfate; and (e) about 0.2% by weight to about

1.0% by weight of magnesium stearate.

In some embodiments, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) 140 mgs of Form A crystalline 1- ((R) -3- (4 amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-1 yl) piperidin-l- ill) prop-2-en-l-one;

(b) 45.9% by weight microcrystalline cellulose;

(c) 7.0% by weight croscarmellose sodium;

(d) 4.2% by weight of sodium lauryl sulfate; and (e) 0.5% by weight of magnesium stearate.

In some embodiments, provided herein is a pharmaceutical formulation for oral administration which comprises:

(a) 140 mgs of Form A crystalline 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-1 ill) piperidin- l-ill) prop-2-en-l-one;

(b) 151.4 mgs of microcrystalline cellulose;

(c) 23.0 mgs of croscarmellose sodium;

14.0 mgs of sodium lauryl sulfate; and (e) 1.6 mgs of magnesium stearate.

In another aspect provided herein is a pharmaceutical formulation which comprises: a) about 40 mgs to about 200 mgs of 1 ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4d] pyrimidin-l-ill) piperidin-l-ill) prop-2-en-l-one; b) about 40% by weight to about 50% by weight of a diluent; c) about 3% by weight to about 10% by weight of a disintegrating agent; d) about 2% by weight to about 7% by weight of a surfactant; and e) about 0.2% by weight to about 1.0% by weight of a lubricant; wherein the formulation is in unit dose form in a blister pack and said blister comprises metal or plastic cloth. In some embodiments, it is a pharmaceutical formulation which comprises: a) 140 mgs of l - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-l -ill) piperidin-lill) prop-2-en-l-one; b) 45.9% by weight of microcrystalline cellulose; c) 7.0% by weight of croscarmellose sodium; d) 4.2% by weight of sodium lauryl sulfate; and e) 0.5% by weight of magnesium stearate where the formulation is in a unit dose form in a blister and said blister institute mixican. DE LA PWl WU> ad INDUSTRIAL comprises metal or plastic cloth.

In another embodiment, it is a package comprising one or more discrete blister packs, where each blister pack comprises a unit dose form which comprises:

a) about 40 mgs to about 200 mgs of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4d] pyrimidin-l-ill) piperidin-l- ill) prop-2-en-l-one;

b) about 40% by weight to about 50% by weight of a diluent; c) about 3% by weight to about 10% by weight of a disintegrating agent; d) about 2% by weight to about 7% by weight of a surfactant; Y

e) about 0.2% by weight to about 1.0% by weight of a lubricant;

where each blister pack comprises metal or plastic cloth.

In another aspect provided herein is a pharmaceutical formulation which comprises: a) about 40 mgs to about 200 mgs of Form A crystalline 1 - ((R) -3- (4-amino-3- (4- phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-ill) piperidin-l-ill) prop-2-in-canvas; b) about 40% by weight to about 50% by weight of a diluent; c) about 3% by weight to about 10% by weight of an agent

IMPie _ ΙΝΓΓΓΤυΤ © MEXICAN ΐζ

OF PROPERTY V

INFUSTPIAL disintegrator; d) about 2% by weight to about 7% by weight of a surfactant; and e) about 0.2% by weight to about 1.0% by weight of a lubricant; wherein the formulation is in a unit dose form in a blister pack and said blister comprises metal or plastic cloth. In some embodiments, it is a pharmaceutical formulation which comprises: a) 140 mgs of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4d] pyrimidin-l -ill) piperidin-l-ill) prop-2-en-l-one; b) 45.9% by weight of microcrystalline cellulose; c) 7.0% by weight of croscarmellose sodium; d) 4.2% by weight of sodium lauryl sulfate; and e) 0.5% by weight of magnesium stearate where the formulation is in unit dose form in a blister and said blister comprises metal or plastic cloth.

In another embodiment, it is a package comprising one or more discrete blister packs, where each blister pack comprises a unit dose form which comprises:

a) about 40 mgs to about 200 mgs of crystalline Form Ά of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l -ill) piperidin-lill) prop-2-en-l-one;

b) about 40% by weight to about 50% by weight of a diluent; c) about 3% by weight to about 10% by weight of an agent

<img file="MX348290B_D0020.tif" />

IMPI

IMTIHiTr. mmican,, θϊ LA PRONEDAD industrial disintegrador; d) about 2% to about 7% by weight of a surfactant; and weight up

e) about 0.2% by weight to about 1.0% by weight of a lubricant;

where each blister pack comprises metal or plastic cloth.

In one embodiment, a kit is provided that contains a multiplicity of the oral dosage forms, such as tablets or capsules, packaged such as a bottle containing the oral dosage forms and instructions for use for administering the oral dosage forms. according to the method described in this document. Unit dose packages such as blister packs provide a useful way of packaging the oral dosage form of the formulation described herein and in other embodiments kit is incorporated when combined with instructions for use. In other embodiments, detailed product information is included with the instructions for use on the kit. The blister pack is particularly useful for solid oral dosage forms and in further embodiments are useful for every other day dosing schedules, for example. In one embodiment, the solid unit dose forms of the formulations described herein included in a blister pack.

ΡI ν / INSTITUTO MfiXiCANl. ύ

Say LA fKLLULJAL '___. _x___________ __ _ _j _._ · ^ _ z x. , '^ DUmiAL with instructions to administer one or more tablets or capsules on a daily basis so that the dose of' the "" formulations described herein are sufficiently administered. In another embodiment, the solid unit dose forms are included in a blister pack with instructions to administer one or more tablets or capsules on an alternate day schedule so that the dose per day is sufficiently administered.

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

In another aspect, provided herein is the use of Compound 1 to inhibit Bruton's tyrosine kinase (Btk) activity or for the treatment of a disease, disorder or condition that would benefit from the

<img file="MX348290B_D0021.tif" />

MEilCAN INSTITUTE

OF THE INDUSTWAL NO PROPERTY Inhibition of Bruton's Tyrosine Kinase (Btk) Activity.

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

In some embodiments, crystalline Compound 1 is administered orally.

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

In one aspect, provided herein is a method of treating cancer in a mammal which comprises administering to the mammal a pharmaceutical composition described herein comprising Compound 1. In some embodiments, the cancer is a malignancy of the cells B. In some embodiments, the cancer is a B-cell malignancy selected from chronic lymphocytic leukemia (CLL) / small cell lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma. In some embodiments, the cancer is lymphoma, leukemia, or solid tumor. In some embodiments, the cancer

IMPI (Ν5ΤΓΠΠΌ MEXICAN η η OS THE PROPERTY

Or industrial is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, prolymphocytic B-cell leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, Extranodal marginal zone B-cell lymphoma, Nodal marginal zone B-cell lymphoma, Mantle cell lymphoma, Mediastinal large B-cell (thymic) lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis. In some embodiments, when the subject is suffering from cancer, a carcinostatic agent is administered to the patient in addition to the aforementioned compounds. In one embodiment, the carcinostatic agent is a mitogen-activated protein kinase signaling inhibitor.

In one aspect, provided herein is a method of treating an inflammatory or autoimmune disease in a mammal which comprises administering to the mammal a pharmaceutical composition described herein comprising Compound 1. In some embodiments, the inflammatory disease is asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis,

ΙΜΡΙ £

MEXICAN INSTITUTE »> 5. ~ “INDUSTRIAL PROPERTY '• i cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, suppurative hydradenitis, laryngitis, mastitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis or vulvitis. In some embodiments, the autoimmune disease is inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves disease, Syndrome. Sjógren's, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, Antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis,

<img file="MX348290B_D0022.tif" />

Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm-type autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, universal alopecia, Behget's disease, chronic fatigue, dysautonomia, 5 endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvodynia. ,

Articles of manufacture are provided including packaging material, Compound 1 within the packaging material and a label indicating that Compound 1 is used to inhibit the activity of tyrosine (s) kinase (s), such as Btk.

In a further aspect, provided herein is a method of treating an autoimmune disease in a mammal, which comprises administering Compound 1 to the mammal.

In a further aspect, provided herein is a method of treating a heteroimmune disease or disorder in a mammal, which comprises administering Compound 1 to the mammal.

In a further aspect, provided herein is a method of treating an inflammatory disease in a mammal, which comprises administering Compound 1 to the mammal.

In a further aspect, provided herein

<img file="MX348290B_D0023.tif" />

document a method

IMPI "®8" for cancer treatment, which comprises the administration of Compound 1 to the mammal.

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

In another aspect, modulation methods are provided, including irreversible inhibition of the activity of Btk or other tyrosine kinases, where the other tyrosine kinases share homology with Btk having a cysteine ​​residue (including a Cys 481 residue) that can form a covalently binding to Compound 1, in a mammal, which comprises administering to the mammal at least once an effective amount of Compound 1. In another aspect, modulation methods, including irreversible inhibition of Btk activity in a mammal, comprising

<img file="MX348290B_D0024.tif" />

IMPI

MLXICANO INSTITUTE

Industrial M LA * administering to the mammal at least once an effective amount of Compound 1. In another aspect, methods for treating Btk-dependent or Btk-mediated disorders or diseases, which comprises administering to the mammal at least once an effective amount of the Compound 1.

In another aspect methods for treating inflammation are provided which comprise administering to the mammal at least once an effective amount of Compound 1.

A further aspect are methods for treating cancer which comprise administering to the mammal at least once an effective amount of Compound 1. The type of cancer may include, but is not limited to, pancreatic cancer and other solid or hematological tumors.

In another aspect methods for treating respiratory diseases are provided which comprise administering to the mammal at least once an effective amount of Compound 1. In a further embodiment of this aspect, the respiratory disease is asthma. In a further embodiment of this aspect, respiratory disease includes, but is not limited to, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood asthma, asthma -to variant asthma, occupational asthma, spheroid-resistant asthma, seasonal asthma.

In another aspect, methods of preventing rheumatoid arthritis and / or osteoarthritis are provided which comprise administering to the mammal at least once an effective amount of Compound 1.

In another aspect methods are provided for treating inflammatory responses of the skin which comprise administering to the mammal at least once an effective amount of Compound 1. Such inflammatory responses of the skin include, by way of example, dermatitis, contact dermatitis, eczema, hives, rosacea and scarring. In another aspect, methods are provided for the reduction of psoriatic lesions in the skin, joints or other tissues or organs, which comprise administering to the mammal an effective amount of Compound 1.

In another aspect the use of Compound 1 is provided in the manufacture of a medicament for treating an inflammatory disease or disorder in an animal in which the activity of Btk or other tyrosine kinases, where the other tyrosine kinases share homology with Btk by having a cysteine ​​residue (including a Cys 481 residue) that can form a covalent bond with at least one inhibitor

<img file="MX348290B_D0025.tif" />

to irreversible described herein, 'the pathology and / or symptoms of the disease or disorder. In one embodiment of this aspect, the protein tyrosine kinase is Btk. In another embodiment of this aspect or in a further embodiment, the inflammatory disease or disorders are respiratory, cardiovascular, or proliferative diseases.

In any of the aforementioned aspects there are additional embodiments in which the

Compound 1 is (a) administered systemically to the mammal;

(b) administered orally to the mammal; (c) administered intravenously to the mammal; (d) administered by inhalation; (e) administered orally; or (f) administered by injection to the mammal; (g) administered topically (dermally) to the mammal; (h) administered by the ophthalmic route; or (i) administered rectally to the mammal.

In any of the aforementioned aspects there are additional embodiments that comprise a single administration of Compound 1, including additional embodiments in which Compound is administered to them (i) once; (ii) multiple times in the course of a day; (iii) continuously; or (iv) continuously.

In any of the aspects mentioned above are additional embodiments that comprise multiple administrations of the Compound. ¹ including, additional embodiments in which (i) Compound 1 is administered in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) Compound 1 is administered to the mammal every 8 hours. In additional or alternative embodiments, the method comprises a drug break, where the administration of Compound I is temporarily suspended or the dose of Compound 1 that is administered is temporarily reduced; At the end of the drug break, the dose of Compound 1 is resumed. The duration of the drug break can range from 2 days to 1 year.

In some embodiments, in any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.), compound 1, or a pharmaceutically acceptable salt or its solvate, is: optically pure (ie i.e. greater than 99% chiral purity by HPLC). In some embodiments, in any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.), Compound 1, or a pharmaceutically acceptable salt or its solvate, is replaced with: a) Compound 1, or a pharmaceutically acceptable salt or its solvate, of lower chiral purity; b) 1 - ((S) -3- (4-amino-3IMPIOS. INSTITUTO MEXICANO

7 OF LA Pt ^ ItlMD CVl .iC-Ój industrial (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-l-ill) piperidinl-ill) prop-2-en-l-one or an acceptable salt pharmaceutically or its solvate of any optical purity; oc) racemic 1- (3- (4 amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-1 yl) piperidin-l-ill.) prop-2-en-l-one or a pharmaceutically acceptable salt or its solvate.

In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.), amorphous Compound 1 is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.), crystalline Compound 1 is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.), crystalline Compound 1 (Form A) is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.), crystalline Compound 1 (Form B) is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.), crystalline Compound 1 (Form C) is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.),

<img file="MX348290B_D0026.tif" />

IMPI

MSXICAN INSTITUTE OF INDUSTRIAL FROHITY uses crystalline Compound 1 (Form D). In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.), crystalline Compound 1 (Form E) is used. In any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.), crystalline Compound 1 (Form F) is used.

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

Other objects, characteristics and advantages of the methods

<img file="MX348290B_D0027.tif" />

and compositions described herein will be apparent from the following detailed description. It should be noted, however, that the detailed description and specific examples, while indicating specific embodiments, are provided by way of illustration only, since various changes and modifications within the spirit and scope of this disclosure will be obvious to skilled persons. on technology from detailed description. The headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are expressly incorporated in their entirety into this document by reference for any purpose.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specification are incorporated herein by reference as long as pertinent and relevant.

BRIEF DESCRIPTION OF FIGS.

Fig. 1. Illustrates an X-ray diffraction pattern (XRPD) of Form A.

Fig. 2. Illustrates an infrared (IR) spectrum of the

Form A.

Fig. 3. Illustrates a DSC thermogram of Form A.

Fig.

4.

Illustrates thermogravimetric analysis (TGA) thermogram of Form A.

Fig. 5. Illustrates an X-ray diffraction pattern (XRPD) of Form B.

Fig. 6. Illustrates an infrared (IR) spectrum of Form B.

Fig. 7. Illustrates a DSC thermogram of Form B.

Fig. 8. Illustrates a thermogravimetric analysis (TGA) thermogram of Form B.

Fig. 9. Illustrates an X-ray diffraction pattern (XRPD) of Form C.

Fig. 10. Illustrates a DSC thermogram of Form C.

Fig. 11. Illustrates a thermogravimetric analysis (TGA) thermogram of Form C.

Fig. 12. Illustrates an X-ray diffraction pattern (XRPD) of Form D.

Fig. 13. Illustrates a thermogravimetric analysis (TGA) thermogram of Form D.

Fig. 14. Illustrates an X-ray diffraction pattern (XRPD) of Form E.

IMPIg ^ ΙΤΤΗΤΤΟ MUlGAN i

M THE 'DUSnUAL HIORITY> 5 51

Fig. 15. Illustrates a DSC thermogram and a ^ íULiuuijiίΐιιΐυΐ ι.ΐι— thermogravimetric analysis (TGA) of Form E.

Fig. 16. Illustrates a simulated X-ray diffraction pattern (XRPD) of Form F.

DETAILED DESCRIPTION OF THE INVENTION

The various roles that Btk signaling plays in various hematopoietic cellular functions, e.g., activation of B cell receptors, suggests that small molecule Btk inhibitors, such as Compound 1, are useful in reducing the risk of - or to treat - a variety of diseases affected by numerous cell types of hematopoietic lineage including, eg, autoimmune diseases, heteroimmune disorders or diseases, inflammatory diseases, cancer (eg, B-cell proliferative disorders), and thromboembolic or B-cell disorders . Additionally, irreversible Btk inhibitory compounds, such as Compound 1, can be used to inhibit a small subset of other tyrosine kinases that share homology with Btk by having a cistern residue (including a Cys 481 residue) that can form a covalent bond. with the irreversible inhibitor.

In some embodiments, Compound 1 can be used in the treatment of an autoimmune disease in a mammal,

<img file="MX348290B_D0028.tif" />

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY which includes, but is not limited to, arthritis * ..... psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis,

Graves, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpast syndrome Idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu arteritis, temporal arteritis, Warm type autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behpet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma and vulvodynia.

In some embodiments, Compound 1 can be used in the treatment of a heteroimmune disease or disorder in a mammal, including, but not limited to, graft-versus-host disease, transplantation, transfusion, anaphylaxis, allergies (eg, allergies to plant pollen, latex, drugs, foods, insect poisoning, animal skin, animal dander, dust mites or calyx

<img file="MX348290B_D0029.tif" />

IMPI

INSTITUTE MEJUCAN *

Dt THE INDUSTRIAL PROPERTY cockroach), type I hypersensitivity, pnnjnntivitío aiórnir.a.

allergic rhinitis and atopic dermatitis.

In some embodiments, Compound 1 may be used in the treatment of an inflammatory disease in a mammal, including, but not limited to, asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myocarditis myelitis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis and vulvitis.

In still other embodiments, the methods described herein can be used to treat cancer, eg, B cell proliferative disorders, including but not limited to diffuse large B cell lymphoma, follicular lymphoma, lymphocytic lymphoma. σΓ0ηίσο,

<img file="MX348290B_D0030.tif" />

ΙΜΡΪ

MEXICAN INSTITUTE

CURRENCY industrial chronic lymphocytic leukemia, B-cell prclinfcirritic leukemia, lymphoplasmacytic lymphoma / macroglobulinemia of

Waldenstrom, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal cell lymphoma Large B (thymic), intravascular large B-cell lymphoma, primary effusion lymphoma, burkitt's lymphoma / leukemia, and lymphomatoid granulomatosis.

In additional embodiments, the methods described herein can be used to treat thromboembolic disorders, including, but not limited to myocardial infarction, angina pectoris (including unstable angina), reocclusions or restenosis after angioplasty or aortocoronary bypass, sudden attack, transient ischemia, peripheral arterial occlusive disorders, pulmonary embolisms and deep vein thrombosis.

Hematologic malignancies

Disclosed herein, in certain embodiments, is a method of treating a hematologic malignancy in an individual in need thereof, which comprises: administering to the individual an amount of the

Compound 1.

<img file="MX348290B_D0031.tif" />

IMPI

INSTITUTO MEXICANO DE LA M '> Hf DAD industrial

In some embodiments, the h ^ Ti-nigic malignancy is non-Hodgkin's lymphoma (NHL). In some embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL), small cell lymphocytic lymphoma (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some embodiments, the hematologic malignancy is follicular lymphoma (EL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma (MM), marginal zone lymphoma, Burkitt's lymphoma, high-grade B-cell non-Burkitt lymphoma, or extranodal marginal zone B-cell lymphoma. In some embodiments, the hematologic malignancy is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or acute B-cell precursor lymphoblastic leukemia. In some embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, the hematologic malignancy is mantle cell lymphoma (MCL). In some embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematologic malignancy is a diffuse large B-cell lymphoma (DLBCL), subtype GCB.

IMPI

In some embodiments, the hematologic malignancy is Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematologic malignancy is multiple myeloma (MM). In some embodiments, the hematologic malignancy is Burkitt's lymphoma. In some embodiments, the hematologic malignancy is follicular lymphoma (EL). In some embodiments, the hematologic malignancy is transformed follicular lymphoma. In some embodiments, the hematologic malignancy is marginal zone lymphoma.

In some embodiments, the hematologic malignancy is relapsed or refractory non-Hodgkin's lymphoma (NHL). In some embodiments, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma (MCL), relapsed or refractory follicular lymphoma (EL), relapsed CLL, or refractory, relapsed or refractory SLL, relapsed or refractory multiple myeloma, relapsed or refractory Waldenstrom's macroglobulinemia, relapsed or refractory multiple myeloma (MM), Recurrent or refractory marginal zone lymphoma, recurrent or refractory Burkitt lymphoma, relapsed or refractory high-grade B-cell non-Burkitt lymphoma, relapsed or refractory extranodal marginal zone B-cell lymphoma.

In some embodiments the malignancy

<img file="MX348290B_D0032.tif" />

IMPI

INSTITUTO MEXICANO t> E THE hematological INDUSTRIAL PROPERTY is myelogenous leukemia (or chronic myeloidéj atjticta — σ chronic in relapse or refractory, relapsed or refractory myelodysplastic syndrome, relapsed or refractory acute lymphoblastic leukemia or acute precursor lymphoblastic lymphoblastic leukemia in the Refractory In some embodiments, the hematologic malignancy is relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the hematologic malignancy is relapsed or refractory mantle cell lymphoma (MCL). In some embodiments, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some embodiments, the hematologic malignancy is relapsed or refractory Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematologic malignancy is relapsed or refractory multiple myeloma (MM). In some embodiments, the hematologic malignancy is relapsed or refractory Burkitt's lymphoma. In some embodiments, the hematologic malignancy is relapsed or refractory follicular lymphoma (FL).

IMPIS _ „X'TITUTc MEXICANO 58 04 1A PROPERTY VE *

INDUSTRIAL

In some embodiments, the hematologic malignancy is a hematologic malignancy classified as high risk. In some embodiments, the hematologic malignancy is high-risk CLL or high-risk SLL.

B-cell lymphoproliferative disorders (BCLD) are neoplasms of the blood and include, inter alia, non-Hodgkin lymphoma, multiple myeloma, and leukemia. BCLDs can originate in either lymphatic tissues (as in lymphoma) or in the bone marrow (as in leukemia and myeloma), and all participate in the uncontrolled growth of lymphocytes or white blood cells. There are numerous subtypes of BCLD, eg, chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). The course of the disease and the treatment of BCLD depends on the subtype of BCLD; however, even within each subtype, the clinical presentation, morphological appearance, and response to therapy are heterogeneous.

Malignant lymphomas are neoplastic cell transformations that reside predominantly within lymphoid tissues. Two groups of malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphomas infiltrate the reticuloendothelial tissues. However, they differ in the neoplastic cell of origin, site of disease, presence of systemic symptoms, and

<img file="MX348290B_D0033.tif" />

IMPI ^WSTSK^rY.'Í «fCANO ^{D £} THE INDUSTRIAL PROPERTY response to treatment (Freedman et al., ..... H. ^ gkin'g

Lymphomas Chapter 134, Cancer Medicine, (publication approved by the American Cancer Society, BC Decker Inc.,

Hamilton, Ontario, 2003).

Non-Hodgkin's Lymphomas

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

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

Non-Hodgkin lymphomas (NHL) are a diverse group of predominantly B-cell malignancies. NHL can develop in any organ associated with the lymphatic system, such as the spleen, lymph nodes, or tonsils, and can occur to

<img file="MX348290B_D0034.tif" />

IMPI Mexican iNjrmjTe DE LA PROPERTY industrial any age. Ά NHL often manifests with enlarged lymph nodes, fever, and weight loss. NHL is classified as either B-cell or T-cell NHL. Lymphomas associated with lymphoproliferative disorders after bone marrow or stem cell transplantation are usually B-cell NHL. In the Working Formulation classification scheme, NHL is divided into low, intermediate and high grade categories by virtue of their natural histories (see The Non-Hodgkin's Lymphoma Pathologic

Classification Project,. Cancer 49 (1982): 2112-2135). Low-grade lymphomas are low-grade, with a median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311: 1471-1475). While chemotherapy can induce remissions in most of the 15 low-grade lymphomas, cures occur rarely and most patients eventually relapse and additional therapies are required. Intermediate and high-grade lymphomas are more aggressive tumors but have a greater chance of being cured through chemotherapy.

However, a significant proportion of these patients will relapse and require additional treatment.

A non-exhaustive list of B-Cell NHL includes Burkitt's lymphoma (eg, endemic Burkitt's lymphoma and

Sporadic Burkitt lymphoma), cutaneous lymphoma of the

<img file="MX348290B_D0035.tif" />

MEXICAN IMPI IMSTITUTu of industrial property 61.

B cells, cutaneous marginal zone lymphoma ~ n^or-llL), diffuse large cell lymphoma —___ (DLBCL), diffuse mixed small and large cell lymphoma, diffuse small cleft cell lymphoma, diffuse small cell lymphocytic lymphoma, extranodal zone B cell lymphoma marginal, follicular lymphoma, follicular small cleft cells (Category 1), follicular mixed cleft cells and large cells (Category 2), follicular large cells (Category 3), intravascular large B-cell lymphoma, Intravascular lymphomatosis, immunoblastic large cell lymphoma, large cell lymphoma (LCL), lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma (MCL), immunoblastic large cell lymphoma, B-precursor B-cell lymphoblastic lymphoma, Mantle cell lymphoma, chronic lymphocytic leukemia (CLL) / small cell lymphocytic lymphoma (SLL), extranodal marginal zone B-cell lymphoma, Mucosa-Linked Lymphoid Tissue Lymphoma (MALT), Mediastinal Large B-Cell Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Splenic Marginal Zone B-Cell Lymphoma, Primary Mediastinal B-Cell Lymphoma, Lymphoma lymphoplasmacytic, whipworm leukemia, Waldenstrom's macroglobulinemia, and primary central nervous system (CNS) lymphoma. Non-lymphomas are contemplated

<img file="MX348290B_D0036.tif" />

IMPI

MEXICAN INSTITUTE

DF LA FROMFD *

INDUSTRIAL

Additional Hodgkin's are within the scope of the present invention and are obvious to the person skilled in the art.

DLBCL

Disclosed herein is, in certain embodiments, a method of treating a DLCBL in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. Further disclosed herein, in certain embodiments, a method of treating relapsed or refractory DLCBL in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

As used herein, the term "diffuse large B cell lymphoma (DLBCL)" refers to a neoplasm of germinal center B lymphocytes with a diffuse growth pattern and a high-intermediate proliferation rate. DLBCLs represent approximately 30% of all lymphomas and can present with several morphological variants including centroblastic, immunoblastic, T-cell / histiocyte-rich, anaplastic, and plasmoblastic subtypes. Genetic testing has shown that there are different subtypes of DLBCL. These subtypes appear to have different perspectives (prognosis) and responses to treatment. DLBCL can affect

IMPI Mexican institute Di LA FR 'PISPAD INDUSTRIAL any age group but appears mainly in older people (the average age is the middle of the sixth decade of life).

Disclosed herein is, in certain embodiments, a method of treating diffuse large B-cell lymphoma, activated B-cell-like subtype (ABC-DLBCL), in an individual in need thereof, which comprises: administering to the individual a irreversible inhibitor of Btk in an amount from 300 mg / day up to and including 1000 mg / day. The diffuse large B-cell lymphoma ABC subtype (ABC-DLBCL) is believed to arise from posterior germinal center B cells that are arrested during plasma differentiation. The ABC subtype of DLBCL (ABCDLBCL) represents approximately 30% of all DLBCL diagnoses. It is considered the least curable of the molecular DLBCL subtypes, and as such, patients diagnosed with ABC-DLBCL typically exhibit significantly lower survival rates compared to individuals with other types of DLCBL. ABC-DLBCL is most frequently associated with chromosomal rearrangements that deregulate the germinal core master regulator BCL6 and with mutations that turn off the PRDM1 gene, encoding a transcriptional repressor required for cell differentiation.

<img file="MX348290B_D0037.tif" />

IMPI

MEXICAN INSTITUTE

Dt THE PROPERTY iNousmiAi

A particularly relevant signaling pathway in the pathogenesis of ABC-DLBCL is that mediated by the nuclear transcription factor (NF) -kB complex. The NF-kB family comprises 5 members (p50, p52, p65, c-rel and RelB) that form homodimers and heterodimers and function as transcription factors to mediate a variety of proliferative, apoptosis, inflammatory and immune responses and are critical for the normal development of B Cells and their survival. NF-κΒ is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, numerous different types of human tumors have an incorrectly regulated NF-kB: that is, NF-κΒ is constitutively active. Active NF-κΒ enables the expression of genes that maintain cell proliferation and protect the cell from conditions that would otherwise cause its death through apoptosis.

The dependence of ABC DLBCL on NF-kB depends on an upstream signaling pathway of IkB kinase composed of CARD11, BCL10, and MALT1 (the CBM complex). Interference with the CBM pathway extinguishes NF-kB signaling in ABC DLBCL cells and induces apoptosis. The molecular basis for the constitutive activity of the NF-kB pathway is currently the subject of investigation but certain somatic alterations to the ABC DLBCL genome clearly invoke this pathway. For example, somatic mutations of the double-spiral domain of CARD11 in DLBCL cause this signaling support protein to spontaneously nuclear the protein-protein interaction with MALT1 and BCL10, causing IKK activity and NF-kB activation. The constitutive activity of the B cell receptor signaling pathway has been implicated in the activation of NF-kB in ABC DLBCL with the wild type CARD11 and is linked to mutations within the cytoplasmic tails of the cell receptor subunits B CD7 9A and CD79B. Oncogenic activation mutations in the MYD88 signaling adapter activate NF-kB and synergize with B cell receptor signaling in support of ABC DLBCL cell survival. Additionally, knockout mutations in a negative regulator of the NF-kB pathway, A20, appear almost exclusively in ABC DLBCL.

In fact, genetic alterations that affect multiple components of the NF-κΒ signaling pathway have been recently identified in more than 50% of ABC-DLBCL patients, where these lesions promote constitutive activation of NF-κΒ, thereby contributing to to the growth of lymphoma. This includes mutations of CARD11 (-10% of cases), a lymphocyte-specific cytoplasmic adapter protein that — together with MALT1 and BCL10 — form the BCR signalosome, which relays signals from antigen receptors to downstream mediators. of NF-κΒ activation. An even larger fraction of cases (~ 30%) carry biallelic genetic lesions that inactivate the A20 negative NF-κΒ regulator. Additionally, high levels of expression of NF-κΒ target genes have been observed in ABC-DLBCL tumor samples. See, eg, U. Klein et al., (2008), Nature Reviews Immunology 8: 22-23; RE Davis et al., (2001), Journal of Experimental Medicine 194: 1861-1874; G.

Lentz et al., (2008), Science 319: 1676-1679; M. Compagno et al., (2009), Nature 459: 712-721; and L. Srinivasan et al., (2009), Cell 139: 573-586).

DLBCL cells of the ABC subtype, such as OCI15 LylO, have chronic active BCR signaling and are highly sensitive to the Btk inhibitor described herein. The irreversible inhibitor of Btk described herein potently and irreversibly inhibits the growth of OCI-LylO (EC₅or continuous exposure - 10 nM, EC50 pulse 1 hour = 50 nM). Furthermore, the induction of apoptosis, as shown by capsase activation, Annexin-V flow cytometry, and increase in sub-GO fraction is observed in OCILylO. Both sensitive and resistant cells express Btk at similar levels and the site

LMPi to INSTITUTO MEXICANO VíSíí

OF THE INDUSTRIAL WOHID r &lt;Z7 active Btk is completely occupied by pUinhihidnr in both, as shown through a fluorescence-labeled affinity probe. OCI-LylO cells are shown as chronically active BCR by signaling NF-kB which is inhibited on a dose basis by the Btk inhibitor described herein. The activity of the Btk inhibitors in the cell lines studied in this document is also characterized by comparing the signal transduction profiles (Btk, PLCy, ERK,

NF-kB, AKT), cytokine secretion profiles and mRNA expression profiles, both with and without BCR stimulation, and significant differences were observed in these profiles that lead to clinical biomarkers that identify the patient populations most sensitive to treatment with Btk inhibitor. See US Patent: No. 7,711,492 and Staudt et al., Nature, Vol. 463, Jan. 7, 2010, pp. 88-92, content which is incorporated in its entirety herein by reference.

Follicular lymphoma

Disclosed herein, in certain embodiments, is a method of treating follicular lymphoma in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. Further disclosed herein, in certain

<img file="MX348290B_D0038.tif" />

BIT

IMPI

INSTITUTO MEXICANA> DE LA MONEDAD INDUSTRIAL embodiments, a method for treating relapsed or refractory follicular lymphoma in an individual in need, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

As used herein, the term "follicular lymphoma" refers to any of several types of non-Hodgkin's lymphoma in which the lymphoma cells are grouped in 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 approximately 60 years.

CLL / SLL

Disclosed herein is, in certain embodiments, a method of treating a CLL or SLL in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. Further disclosed herein, in certain embodiments , a method of treating relapsed or refractory CLL or SLL in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

Chronic lymphocytic leukemia and small cell lymphocytic lymphoma are often thought to

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IMPI ινγγγπγγο Mexican OBLA MONEDAD INDUSTRIAL (CLL / SLL) are the same disease with slightly different manifestations. The site where cancer cells gather determines whether it is called CLL or SLL. When cancer cells are found primarily in the 5 lymph nodes, lima bean-shaped structures of the lymphatic system (a primarily small vessel system found in the body),_s it is called SLL. SLL constitutes approximately 5% to 10% of all lymphomas. When the majority of cancer cells are in the 10 bloodstream and bone marrow, it is called CLL.

Both CLL and SLL are slow-growing diseases, although the much more common CLL tends to grow more slowly. CLL and SLL are treated in the same way. They are generally not considered curable with the 15 conventional treatments, but depending on the stage and rate of growth of the disease, most patients live for more than 10 years. Occasionally, over time, these slow-growing lymphomas can develop into a more aggressive type of lymphoma.

Chronic lymphoid leukemia (CLL) is the most common type of leukemia. An estimated 100,760 people in the United States are living with CLL or in remission. The majority (> 75%) of people newly diagnosed with CLL are close in age. at age 50. Currently, the

<img file="MX348290B_D0040.tif" />

IMPI

MEXICAN INSTITUTE

I HEARD INDUSTRIAL PROPERTY treatment for CLL focuses on controlling the disease and its symptoms rather than curing itself. The

CLL is treated with chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (removal 'by splenectomy of the enlarged spleen) or by radiation therapy (deflating of swollen glands). Although CLL progresses slowly in most cases, it is generally considered incurable. Certain CLLs have been classified as high risk. As used herein, "high risk CLL" means CLL characterized by at least one of the following 1) 17pl3-; 2) llq22-; 3) Unmuted IgVH together with ZAP-70 + and / or CD38 +; or 4) trisomial2.

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

Small cell lymphocytic leukemia (SLL) is very similar to CLL described above and is also a B-cell cancer. In SLL, the abnormal lymphocytes mainly affect the lymph nodes. However, in CLL the abnormal cells mainly affect the blood and bone marrow. The spleen can be affected in both

IMPI

INSTITUTO MEZIOkc conditions. SLL constitutes approximately Leu 25 of all non-Hodgkin lymphoma cases. It can appear at any time from early adulthood to old age but is rare before age 50. SLL is considered a low-grade lymphoma. This means that the disease progresses very slowly and patients tend to live for many years after their diagnosis. However, most are diagnosed when the disease is in an advanced stage, and while SLL responds well to a variety of chemotherapy drugs, it is generally considered incurable. While some types of cancer tend to occur more frequently in one gender or another, cases and deaths due to SLL are evenly divided between women and men. The average age at diagnosis is 60 years.

Although SLL has a low degree of malignancy, it progresses persistently. The usual pattern of this disease is one of high response rates to radiation therapy and / or chemotherapy with a period of remission of the disease. This is followed months or years later by an inevitable relapse. Repetition of the treatment leads to a response again but again recurrence will occur. This means that while the short-term forecast for SLL is highly satisfactory, over time,

<img file="MX348290B_D0041.tif" />

PI

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Μ U INDUSTRIAL PROPERTY many patients develop complications, and recurrent disease. Taking into account the age at which CLL and SLL are normally diagnosed, there is a need for a simple and effective treatment with a minimum of side effects that do not hamper the quality of life of the patient. Instant invention fulfills this longstanding need within technology.

Mantle cell lymphoma

Disclosed herein is, in certain embodiments, a method of treating mantle cell lymphoma in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory mantle cell lymphoma in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

As used herein, the term "Mantle Cell Lymphoma" refers to a subtype of B-cell lymphoma, due to CD5 antigen-positive naive pregerminal center B cells within the mantle zone surrounding the follicles of the normal germinal center. MCL cells generally overexpress Di cyclin due to a t (ll: 14) chromosomal rearrangement in DNA.

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MEXICAN INSTITUTE 7 3 ^w any industrial property

More specifically, the rearrangement is at t (11,14) (ql3; q32). Only about 5% of lymphomas are of this type. The cells are small to medium in size. Most often it affects men. The average age of the patients is in the first years of the sixth decade of life. Lymphoma is usually widespread at the time of diagnosis, involving the lymph nodes, bone marrow, and most often the spleen. Mantle cell lymphoma is not a fast-growing lymphoma, but it is difficult to treat.

Marginal zone B-cell lymphoma

Disclosed herein, in certain embodiments, is a method for treating a marginal zone B-cell lymphoma in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. Further disclosed herein, in certain embodiments, is a method of treating a relapsed or refractory marginal zone B-cell lymphoma in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of the Compound one.

As used herein, the term "marginal zone B-cell lymphoma" refers to a group of related B-cell neoplasms that

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impi * STmrroM_UlCA*

Dt THE MOHIDAC «NDUSTMal involve the lymphoid tissues in the marginal zone; ΐ^{1 ¿} not uniform outside the area of ​​the follicular mantle. Marginal zone lymphoma accounts for approximately 5% to 10% of lymphomas. The cells in these lymph nodes look small under a microscope. There are 3 main types of marginal zone lymphoma including extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, and splenic marginal zone lymphoma.

MALT

Disclosed herein is, in certain embodiments, a method of treating a MALT in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. Further disclosed herein, in certain embodiments, a A method of treating a relapsed or refractory MALT in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

The term "mucosa-linked lymphoid tissue (MALT) lymphoma", as used herein, refers to extranodal manifestations of marginal zone lymphomas. Most MALT lymphomas are low-grade, although a minority either initially manifests as intermediate-grade NHL or progresses

<img file="MX348290B_D0043.tif" />

IMPI

MEXICAN INSTITUTE

Dt THE INDUSTRIAL PROPERTY from the low grade form. Most MALT lymphomas appear in the stomach, and approximately 70% of gastric MALT lymphoma is associated with Helicobacter pylori infection. Several cytogenetic abnormalities 5 have been identified, the most frequent being trisomy 3 or t (ll; 18). Many of these other MALT lymphomas have also been linked to infections with bacteria or viruses. The average age of MALT lymphoma patients is approximately 60.

Nodal marginal zone B-cell lymphoma

Disclosed herein is, in certain embodiments, a method of treating nodal marginal zone B-cell lymphoma in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory marginal zone B-cell nodal lymphoma in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

The term marginal zone B-cell nodal lymphoma refers to a low-grade B-cell lymphoma that is found primarily in the lymph nodes. The disease is rare and only constitutes

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MEXICAN INSTITUTE.

UF PROPERTY VT ^ -Ώ · í γ g INDUSTRIAL 1% of all non-Hodgkin lymphomas (NHL). -111070 ^ = 1 + ί ca more frequently in older patients, with women being more susceptible than men. The disease is classified as a marginal zone lymphoma because the mutation occurs in the marginal zone of B cells. Due to the confinement in the lymph nodes, the disease is also classified as nodal.

Splenic marginal zone B-cell lymphoma

Disclosed herein, in certain embodiments, is a method of treating splenic marginal zone B-cell lymphoma in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. Further disclosed herein is, in certain embodiments, a method of treating a relapsed or refractory splenic marginal zone B-cell lymphoma in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

The term splenic marginal zone B-cell lymphoma refers to a specific low-grade small B-cell lymphoma incorporated into the World Health Organization classification. The characteristics are splenomegaly, moderate lymphocytosis with hairy morphology, an intrasinusoidal pattern with industrial participation of several organs, especially the bone marrow, and a relative evolution of a low degree of malignancy. In a minority of patients, tumor progression is observed with an increase in blast tumors and aggressive behavior. Molecular and cytogenetic studies have shown heterogeneous results, probably due to the absence of standardized diagnostic criteria.

Burkitt lymphoma

Disclosed herein is, in certain embodiments, a method of treating Burkitt's lymphoma in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. It is further disclosed. herein, in certain embodiments, a method of treating relapsed or refractory Burkitt's lymphoma in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

The term Burkitt's lymphoma refers to a type of Non-Hodgkin's Lymphoma (NHL) that frequently affects children. It is a highly aggressive type of B-cell lymphoma that often begins and develops in parts of the body other than the lymph nodes. Despite its fast-growing nature, Burkitt's lymphoma is often curable with modern intensive therapies. exist

<img file="MX348290B_D0044.tif" />

Two broad types of Burkitt lymphoma - sporadic and endemic varrtee:

Endemic Burkitt Lymphoma: The disease affects children much more than adults and is related to Epstein Barr Virus (EBV) infection in 95% of cases. It occurs mainly in equatorial Africa, where about half of all childhood cancer cases are Burkitt's lymphoma. It is characterized by a high probability of affecting the jaw, a rather peculiar characteristic that is rare in sporadic Burkitt lymphoma. The abdomen is often affected as well.

Sporadic Burkitt's Lymphoma: The type of Burkitt's Lymphoma that affects the rest of the world, including Europe and the Americas is the sporadic type. Also in this case, it is mainly a childhood disease. The link between the Epstein Barr Virus (EBV) is not as strong as it is with the endemic variety, although direct evidence of EBV infection is present in one in five patients. More than affecting the lymph nodes, it notably affects the abdomen in more than 90% of children. Bone marrow involvement is more common than in the sporadic variety.

Waldenstrom's macroglobulinemia

It is disclosed in this document, in certain Mexican wsTmrro OI LA MONEDAD INDUSTRIAL

IMPI embodiments, a method of treating Waldenstrom's macroglobulinemia in an individual in need thereof, which comprises: administering an amount of Compound 1 to the individual. In certain embodiments, a method of treating Waldenstrom's macroglobulinemia is further disclosed herein. Recurrent or refractory Waldenstrom in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

The term Waldenstrom's macroglobulinemia, also known as lymphoplasmacytic lymphoma, is a cancer that affects a subtype of white blood cells called lymphocytes. It is characterized by uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized in that the lymphoma cells make an antibody called immunoglobulin M (IgM). IgM antibodies circulate in the blood in large amounts and make the liquid part of the blood thick like syrup. This can lead to decreased blood flow to many organs, which can lead to vision problems (due to poor circulation in the blood vessels at the back of the eye) and neurological problems (such as headache, dizziness and confusion) caused by low blood flow

<img file="MX348290B_D0045.tif" />

in the brain.

Other symptoms may include tiredness and weakness and a tendency

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ease. The underlying etiology is not completely known but a number of risk factors have been identified, including the 6p21,3 locus on chromosome 6. There is a 2-3 fold increased risk of developing. WM in people who have a personal history of autoimmune diseases with antibodies and particularly elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis. .

Multiple myeloma

Disclosed herein is, in certain embodiments, a method of treating a myeloma in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. Further disclosed herein, in certain embodiments, a method of treating relapsed or refractory myeloma in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

Multiple meloma, also known as MM, myeloma, plasma cell myeloma, or Kahler's disease (by Otto Kahler) is a cancer of the white blood cells known as plasma cells. A type of B cell,

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IMPI

1N5T1TUTÜ ΜΕΧΙΟΑΝ.

FROM INDUSTWAL PROPERTY Plasma cells are a crucial part of the immune system responsible for the production of antibodies in humans and other vertebrates. They are produced in the bone marrow and are transported through the lymphatic system.

Leukemia

Disclosed herein is, in certain embodiments, a method for treating leukemia in an individual in need thereof, which comprises: administering to the individual an amount of Compound 1. Further disclosed herein, in certain embodiments, a A method of treating relapsed or refractory leukemia in an individual in need thereof, which comprises: administering to the individual a therapeutically effective amount of Compound 1.

Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase in blood cells, usually leukocytes (white blood cells). Leukemia is a broad term that covers a spectrum of diseases. The first division is between the acute and chronic forms: (i) acute leukemia is characterized by the rapid growth of immature blood cells. This clumping makes the bone marrow unable to make healthy blood cells. Immediate treatment is required in acute leukemia due to rapid progression and

<img file="MX348290B_D0048.tif" />

They give accumulation of malignant cells, which · into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children; (ii) chronic leukemia is distinguished by the excessive accumulation of relatively mature but still abnormal white cells. Usually months or years in advance, cells are produced at a much faster rate than normal cells, leading to numerous white blood cells in the blood. Chronic leukemia occurs mainly in older people but in theory it can appear in any age group. Additionally, diseases are subdivided according to the type of blood cell affected. This division refers to lymphoblastic leukemias or lymphocytic leukemias and myeloid or myelogenous leukemias: (i) lymphoblastic or lymphocytic leukemias, the cancerous change occurs in a type of marrow cell that normally forms lymphocytes, which are the cells of the immune system to fight the infections; (ii) myeloid or myelogenous leukemias, the cancerous change occurs in a type of marrow cell that normally forms red blood cells, some other types of white blood cells, and platelets.

Within these main categories, there are several subcategories, including, but not limited to, leukemia. • NSTTTUTO MEXICANO DE LA PROP | tD_TOindustrial p

Acute lymphoblastic IMPI (ALL), B-cell precursor acute lymphoblastic leukemia (B-precursor ALL; also called B-cell precursor lymphoblastic leukemia), Acute myelogenous leukemia (AML), Chronic myelogenous leukemia (CML), and Hairy cell leukemia (HCL). Therefore, there is disclosed herein, in certain embodiments, a method of treating acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also called precursor B-cell lymphoblastic leukemia ), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) or whipworm leukemia (HCL) in an individual who needs it, which comprises: administering to the individual an amount of Compound 1. In some embodiments, the leukemia is relapsed or refractory leukemia. In some embodiments, the leukemia is relapsed or refractory acute lymphoblastic leukemia (ALL), B-cell precursor acute lymphoblastic leukemia (BALL precursor; also referred to as relapsed or refractory B-cell lymphoblastic leukemia), acute myelogenous leukemia (AML) relapsing or refractory, relapsing or refractory chronic myelogenous leukemia (CML), or relapsing or refractory hairy cell leukemia (HCL).

Symptoms are known diagnostic tests and prognostic tests for each of the above conditions. See, eg, Harrison's Principles of Internal Medicine®, 16th ed., 2004, The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal 3 (24), and the Revised European American Lymphoma (REAL) classification system (see, eg, the National Cancer Institute website).

A number of animal models are useful in establishing a range of therapeutically effective doses of compounds of an irreversible Btk inhibitor, such as Compound 1, to treat any of the aforementioned diseases.

The therapeutic efficacy of Compound 1 for any of the aforementioned diseases can be optimized during the course of treatment. For example, a subject undergoing treatment may undergo a diagnostic evaluation to correlate relief of symptoms of disease or pathologies with inhibition of in vivo activity of Btk achieved by administration of a given dose of Compound 1. Cellular tests known in the art can be used to determine the in vivo activity of Btk in the presence or absence of an irreversible inhibitor of Btk. For example, since activated Btk is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), the staining

<img file="MX348290B_D0049.tif" />

IMPI

MEXICAN INSTITUTE

Oi PI1223- or P-il551-positive phospho-specific immunocytochemical INDUSTRIAL FMjMMOAD can be used to detect or quantify Bkt activation in a population of cells (eg, by FACS analysis of labeled versus unlabeled cells). See, eg, Nisitani et al. (1999), Proc. Nati. Acad. Sel, USA 96: 2221-2226. Thus, the amount of the Btk inhibitory compound that is administered to a subject can be increased or decreased as necessary to maintain an optimal level of Btk inhibition to treat the subject's disease state.

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

In some embodiments, Compound 1 is used in the manufacture of a medicament for the treatment of any of the foregoing conditions (eg, autoimmune diseases, inflammatory diseases, allergic disorders, B cell proliferative disorders,

<img file="MX348290B_D0050.tif" />

IMPI Mexican institute □ i LA FRWICDAD 'NOUSTmAL or thromboembolic disorders).

Compound 1, and Its Pharmaceutically Acceptable Salts

The Btk inhibitor compound described herein (i.e., Compound 1) is a selective inhibitor of Btk and of the kinases that have a cysteine ​​residue at a position in the amino acid sequence of tyrosine kinase that is homologous to the position in the amino acid sequence of cysteine ​​481 in Btk. The Btk inhibitory compound can form a covalent bond with the Cys 481 of Btk (eg, by a Michael reaction).

Compound 1 or 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) piperidin-l-yl) prop-2-en -l-one or l - {(3R) -3- [4-amino-3- (4-phenoxyphenyl) -Iphi-pyrazolo [3,4d] pyrimidin-l-yl] piperidin-l-yl} prop-2 -en-l-one or 2-Propen15 1-one, 1- [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -l / f-pyrazolo [3,4d] pyrimidin-l- yl] -1-piperidinyl- or ibrutinib or any other suitable name refers to the compound with the following structure:

<img file="MX348290B_D0051.tif" />

<img file="MX348290B_D0052.tif" />

IMPI

INSTITUTO MEXICANO üt LA PRURITIJAD g 7 INDUSTRIAL

A wide variety of pharmaoautically acceptable salts are formed from Compound 1 including:

- acid addition salts formed by reacting Compound 1 with an organic acid, 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. and includes, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid , methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like;

- acid addition salts formed by the reaction of Compound 1 with an inorganic acid, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.

The term "pharmaceutically acceptable salts" in reference to Compound 1 refers to a salt of Compound 1, which does not cause considerable irritation in a mammal to which it is administered and which does not substantially abrogate the

<img file="MX348290B_D0053.tif" />

biological activity and properties of the compound.

Reference to a pharmaceutically acceptable salt will be understood to include solvent addition forms (solvates). Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether ( DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THE), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, and the like. In one aspect, solvates are formed using, but not limited to, Class 3 solvent (s). Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Drugs for Use in Humans. (ICH), Impurities: Guidelines for Residual Solvents, Q3C (R3), (November 2005). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, the solvates of Compound 1, or their pharmaceutically acceptable salts, are conveniently prepared or formed during the processes described herein. In

IMPI

INSTITUTO MEXICANO OI LA MONEDAD industrial some modalities, the solvates of Compound 1 are anhydrous. In some embodiments, Compound 1, or its pharmaceutically acceptable salts, exist in a non-solvated form. In some embodiments, Compound 1, or its pharmaceutically acceptable salts, exist in a non-solvated form and are anhydrous.

In still other embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is prepared in various ways, including but not limited to amorphous phase, crystalline forms, powdered forms, and nanoparticulate forms. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is amorphous and anhydrous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline and anhydrous.

In some embodiments, Compound 1 is prepared as described in US Patent no. 7,514,444.

Compound 1 Amorphous

In some embodiments, Compound 1 is amorphous and anhydrous. In some embodiments, Compound 1 is amorphous. In some embodiments, amorphous Compound 1 has an X-ray Powder Diffraction pattern with no crystallinity.

(XRPD)

<img file="MX348290B_D0054.tif" />

that presents a

Compound 1, Form A

In some embodiments, Compound 1 is crystalline.

In some embodiments, Compound 1 is crystalline Form A. The crystalline Form A of Compound 1 is characterized by having at least one of the following properties:

(a) an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 1;

(b) an X-ray powder diffraction pattern (XRPD) with characteristic peaks at 5,710.1 ° 2-Theta, 13,610.1 ° 2-Theta, 16,110.1 ° 2-Theta, 18,910.1 ° 2-Theta, 21,310 , 1 ° 2Theta, and 21,610.1 ° 2-Theta;

(c) essentially the same pattern of X-ray powder diffraction (XRPD) post storage at 40 ° C and 75% RH for at least one week;

(d) essentially the same pattern of X-ray powder diffraction (XRPD) post storage at 25 ° C and 97%

HR for at least a week;

(e) an infrared (IR) spectrum essentially the same as illustrated in Fig. 2;

(f) weak peaks in the infrared (IR) spectrum at around 1584 cm^-1, about 1240 cm^-1, about

IMPIg ^

INSTITUTO MEXICANO 0 or OF THE PROPERTY O «b» JÍ3sM &amp;

and 1 INDUSTRIAL

1147 cm '¹, about 1134 cm '¹, about 1099 cm '¹, and about 1067 cm^-1;

(g) a DSC thermogram essentially the same as illustrated in Fig. 3;

(h) a thermogram in thermogravimetric analysis (TGA) essentially the same as illustrated in Fig. 4;

(i) a DSC thermogram with an endotherm having a start at around 154 ° C and a peak at around 157 ° C and an exotherm at around 159 ° C;

(j) absence of hygroscopicity;

(k) an observed aqueous solubility of about 0.013 mg / mL at about pH 8;

or (1) their combinations.

In some embodiments, Form A of Compound 1 is characterized by having at least two of the properties selected from (a) to (k). In some embodiments, Compound 1 Form A is characterized as having at least three of the properties selected from (a) to (k). In some embodiments, Compound 1 Form A is characterized as having at least four of the properties selected from (a) to (k). In some embodiments, Compound 1 Form A is characterized as having at least five of the properties selected from (a) to (k). In some modalities, the Form

<img file="MX348290B_D0055.tif" />

iMPi

Compound A is characterized by having at least the selected properties of (a) to (k). In some embodiments, Compound 1 Form A is characterized as having at least seven of the properties selected from (a) to (k). In some embodiments, Compound 1 Form A is characterized as having at least eight of the properties selected from (a) to (k). In some embodiments, Compound 1 Form A is characterized as having at least nine of the properties selected from (a) to (k). In some embodiments, Compound 1 Form A is characterized as having at least ten of the properties selected from (a) to (k). In some embodiments, Form A of Compound 1 is characterized by having the properties (a) to (k).

In some embodiments, Form A has an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 1. In some embodiments, Form A has an X-ray powder diffraction pattern (XRPD). with characteristic peaks at 5,710.1 ° 2-Theta, 13,610.1 ° 2-Theta, 16; 110, l ° 2-Theta, 18,910.1 ° 2-Theta, 21,310.1 ° 2-Theta, and 21,610.1 2-Theta. In some embodiments, Form A has essentially the same X-ray powder diffraction pattern (XRPD) post storage at 40 ° C and 75% RH for at least one week. In some embodiments, Form A has essentially the same X-ray diffraction pattern of

<img file="MX348290B_D0056.tif" />

IMPI Mexican institute CELA HIOMFCAO INDUSTIUAl powders (XRPD) post storage at 25 ° C and 97% RH for at least one week.

In some embodiments, Form A has an infrared (IR) spectrum essentially the same as illustrated in Fig.

2. In some embodiments, Form A has faint peaks in the infrared (IR) spectrum at around 1584 cm¹, about 1240 cm '¹, about 1147 cm '¹, about 1134 cm *¹, about 1099 cm¹, and about 1067 cm¹.

In some embodiments, Form A has a DSC thermogram essentially the same as illustrated in Fig. 3. In some embodiments, Form A has a thermogram on thermogravimetric analysis (TGA) essentially the same as illustrated in Fig. 4 In some embodiments, Form A has a DSC thermogram with an endotherm that has a

fifteen. start at around 154 ° C and a peak at around 157 ° C and an exotherm at around 159 ° C.

In some embodiments, Form A lacks hygroscopicity.

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

In some embodiments, Form A is made from ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK),

<img file="MX348290B_D0057.tif" />

IMPI

MEXICAN INSTITUTE:>

FROM INDUSTRIAL PROPERTY nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole, acetone, heptanes, a methanol / water mixture or an acetone / heptane mixture. In some embodiments, Form A is made from ethyl acetate, isopropyl acetate, tetrahydrofthyran ,.

methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole, acetone, heptanes, or a mixture of acetone / heptane.

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

Compound 1, Form B

In some embodiments, Compound 1 is crystalline.

In some embodiments, Compound 1 is crystalline Form B 15. The crystalline Form B of Compound 1 is characterized by having at least one of the following properties:

(a) an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 5;

(b) an X-ray powder diffraction pattern (XRPD) with characteristic peaks at 5,210.1 ° 2-Theta, 10,210.1 ° 2-Theta, 16,510.1 ° 2-Theta, 18,510.1 ° 2-Theta, and 20,810.1 ° 2Theta;

(c) essentially the same diffraction pattern of

<img file="MX348290B_D0058.tif" />

[MPI uwmrro.MtxicAN, or »Industrial property X-ray powders (XRPD) post storage a_. 40 ° c and 75% of

HR for at least a week;

(d) essentially the same X-ray powder diffraction pattern (XRPD) post storage at 25 ° C and 97% RH for at least one week;

(e) an infrared (IR) spectrum essentially the same as illustrated in Fig. 6;

(f) faint peaks in the infrared (IR) spectrum at around 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 '¹;

(g) a DSC thermogram essentially the same as illustrated in Fig. 7;

(h) a thermogram in thermogravimetric analysis (TGA) essentially the same as illustrated in Fig. 8;

(i) a DSC thermogram with an endotherm having a start at around 99-106 ° C and a peak at around 115-118 ° C;

(j) an observed aqueous solubility of about 0.0096 mg / mL at a pH of about 7.42;

or (k) their combinations.

In some embodiments, Form B of Compound 1 is

ΙΜΡΙ £

Q &amp; ΙΝΉΤυΤΟ MEXICAN

Μ THE INDIVIDUAL MOPltDAO is characterized by having at least two of the properties selected from (a) to (j). In some modalities, the Form

B of Compound 1 is characterized by having at least three of the properties selected from (a) to (j). In some embodiments, Compound 1 Form B is characterized as having at least four of the properties selected from (a) to (j). In some embodiments, Compound 1 Form B is characterized as having at least five of the properties selected from (a) to (j). In some modalities, the Form

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

In some embodiments, Form B has an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 5. In some embodiments, Form B has an X-ray powder diffraction pattern (XRPD). with characteristic peaks at 5.2 ± 0.1 ° 2-Theta

<img file="MX348290B_D0059.tif" />

16.5 ± 0.1 ° 2-Theta,

18.5 ± 0.1 ° 2-Theta,

<img file="MX348290B_D0060.tif" />

In some embodiments, Form B has essentially the same X-ray powder diffraction pattern (XRPD) post storage at 40 ° C and 75% RH for at least one week. In some embodiments, Form B has essentially the same X-ray powder diffraction pattern (XRPD) post storage at 25 ° C and 97% RH for at least one week.

In some embodiments, Form B has an infrared (IR) spectrum essentially the same as illustrated in Fig. 6. In some embodiments, Form B has faint peaks in the infrared (IR) spectrum at around 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^-1.

In some embodiments, Form B has a DSC thermogram essentially the same as illustrated in Fig. 7. In some embodiments, · Form B has a thermogram on thermogravimetric analysis (TGA) essentially the same as illustrated in Fig. 8. In some embodiments, Form B has a DSC thermogram with an endotherm that has a start at around 99-106 ° C and a peak at around 115118 ° C.

IMPIíSg ^

In some embodiments, Form B has an observed aqueous of about 0.0096 mg / 5rtir -'- ^ gjji _ ^^ __ de_ _ about 7.42.

In some embodiments, Form B is made from a mixture of methanol and water.

In some embodiments, Form B is unsolvated. In some embodiments, Form B is anhydrous.

Compound 1, Form C

In some embodiments, Compound 1 is crystalline.

LO In some embodiments, Compound 1 is crystalline Form C. The crystalline Form C of Compound 1 is characterized by having at least one of the following properties:

(a) an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in FIG. 9;

(b) an X-ray powder diffraction pattern (XRPD) with characteristic peaks at 7.010.1 ° 2-Theta, 14.0 + 0.1 ° 2-

Theta, 15,710.1 ° 2-Theta, 18,210.1 ° 2-Theta, 19,110.1 ° 2-Theta, 19,510.1 ° 2-Theta, 20.3 + 0.1 ° 2-Theta, 22.1 + 0, 1 ° 220 Theta, and 22.9 + 0.1 ° 2-Theta;

(c) an essentially equal DSC thermogram illustrated in FIG. 10;

(d) a thermogram on thermogravimetric analysis (TGA) essentially the same as illustrated in Fig. 11;

„ÍMPW

9 MEXICAN INSTITUTE

D £ THE TROHITY tV- ^¹Industrial (e) a DSC thermogram with an endotherm having a start at around 134-135 ° C and a peak at around 137-139 ° C;

or (f) their combinations.

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

In some embodiments, Form C has an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 9. In some embodiments, Form C has an X-ray powder diffraction pattern (XRPD). with characteristic peaks at 7.0 + 0.1 ° 2-Theta, 14,010.1 ° 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, 20,310.1 ° 2-Theta, 22,110.1 ° 2-Theta, and 22.9 + 0.1 ° 2-Theta.

In some embodiments, Form C has a DSC thermogram essentially the same as that illustrated in Fig. 10. In

<img file="MX348290B_D0061.tif" />

In some modalities, Form C has a thermogravimetric analysis (TGA) papncialniont-p equal to that illustrated in Fig. 11. In some modalities, Form C has a thermogram of DSC with an endotherm that has a start at around 134-135 ° C and a peak at around 137-139 ° C.

In some embodiments, Form C is obtained from a mixture of methane! and water. In some embodiments, Form C is made from methanol.

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

Compound 1, Form D

In some embodiments, Compound 1 is crystalline.

In some embodiments, Compound 1 is crystalline Form D. The crystalline Form D of Compound 1 is characterized by having at least one of the following. properties:

(a) an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 12;

(b) an X-ray powder diffraction pattern (XRPD) with characteristic peaks at 7.2 ± 0.1 ° 2-Theta, 8.0 ± 0.1 ° 2 Theta, 9.2 ± 0.1 ° 2 -Theta, 14.5 ± 0, l ° 2-Theta, 18.5 + 0.1 ° 2-Theta, 19.5 ± 0, l ° 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;

ιοί IMPI ^

XSTTTUTu MEXICANO (c) a thermogram in the thermo-gravS3n®tri «JJ (TGA) analysis essentially the same as that illustrated in Fig ·: - o

(d) their combinations.

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

In some embodiments, Form D has an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 12. In some embodiments, Form D has an X-ray powder diffraction pattern (XRPD). with characteristic peaks at 7.2 ± 0.1 ° 2-Theta, 8.0 ± 0, l ° 2-Theta, 9.2 ± 0, l ° 2-Theta, 14.5 + 0.1 ° 2- Theta, 18.5 ± 0, l ° 2-Theta, 19.5 ± 0, l ° 2-Theta, 20.7 ± 0, l ° 2-Theta, 21.0 ± 0, l ° 2-Theta, 21.9 + 0.1 ° 2-Theta, and 22.4 ± 0.1 ° 2-Theta.

In some embodiments, Form D has a thermogram on thermogravimetric analysis (TGA) essentially the same as illustrated in Fig. 13.

In some embodiments, Form D is made from methyl isobutyl ketone (MIBK). In some embodiments, Form D is solvated. In some embodiments, Form D is solvated with methyl isobutyl ketone (MIBK).

102

Compound 1, Form E

In some modalities, the Compound

<img file="MX348290B_D0062.tif" />

In some embodiments, Compound 1 is crystalline Form E. The crystalline Form E of Compound 1 is characterized by having at least one of the following properties:

(a) an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 14;

(b) an X-ray powder diffraction pattern (XRPD) with characteristic peaks at 7.8 + 0.1 ° 2-Theta, 8.8 + 0.1 ° 2Theta, 16.1 ± 0.1 ° 2 -Theta, 18.1 + 0.1 ° 2-Theta, 19.3 ± 0, l ° 2-Theta, 19.5 ± 0, l ° 2-Theta, 20.5 + 0.1 ° 2-Theta, 21 , 6 ± 0.1 ° 2-Theta, and 25.2 ± 0.1 ° 2-Theta;

(c) a DSC thermogram essentially the same as 15 illustrated in Fig. 15;

(d) a thermogram in thermogravimetric analysis (TGA) essentially the same as that illustrated in Fig. 15;

or (e) their combinations.

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

103 In embodiments, the Compound Form E has the properties (a) through (d).

IMPI

INSTITUTO MUICANi • L INDUSTRIAL PROPERTY

<img file="MX348290B_D0063.tif" />

it is characterized by

In some embodiments, Form E has an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 14. In some embodiments, Form E has an X-ray powder diffraction pattern (XRPD). with characteristic peaks at 7.8 ± 0, l ° 2-Theta, 8.8 ± 0, l ° 2-Theta, 16, l ± 0, l ° 2-Theta, 18, l ± 0, l ° 2- Theta, 19.3 ± 0, l ° 2-Theta, 19.5 ± 0, l ° 2-Theta, 20.5 ± 0, l ° 2-Theta, 21.6 + 0.1 ° 2-Theta, and 10 25.2 ± 0.1 ° 2-Theta.

In some embodiments, Form E has a DSC thermogram essentially the same as illustrated in Fig. 15. In some embodiments, Form E has a thermogram on thermogravimetric analysis (TGA) essentially the same as illustrated in Fig. fifteen.

In some embodiments, Form E is made from toluene.

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

Compound 1, Form F

In some embodiments, Compound 1 is crystalline.

In some embodiments, Compound 1 is crystalline Form F. The crystalline Form F of Compound 1 is characterized by having at least one of the following

104 properties:

IMPI

INSTITUTE MtXICAN. >

OS INDUSTRIAL PROPERTY

<img file="MX348290B_D0064.tif" />

(a) an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 16;

(b) An X-ray powder diffraction pattern (XRPD) with characteristic peaks at 6.210.1 ° 2-Theta, 10.1 + 0.1 ° 2-Theta, 17.6 + 0.1 ° 2- Theta, 18.6 + 0.1 ° 2Theta, 20.010.1 ° 2-Theta, 20.4 ± 0, l ° 2-Theta, 20.7 ± 0, l ° 2-Theta, 22.4 ± 0, l ° 2-Theta, 23.0 + 0.1 ° 2-Theta, 23.2 + 0.1 ° 2-Theta, 24.4 ± 0, l ° 2-Theta, 25.1 + 0.1 ° 2Theta, 27.6 + 0.1 ° 2-Theta, 29,310.1 ° 2-Theta, and 29,710.1 ° 2-Theta;

(c) Unit cell parameters essentially equal to the following at 100 (2) K:

<td>System crystalline</td><td colspan="5">Triclinic</td>

<td rowspan="3">Group space</td><td rowspan="3">P1</td><td>to</td><td>9.6332 (3) TO</td><td> □</td><td> 105,762(3)°</td>

<td>b</td><td>9.7536 (4) TO</td><td> □</td><td> 95,132 (2)°</td>

<td>c</td><td>15, 0592 (4) TO</td><td> □</td><td> 111,332(3)°</td>

<td>V</td><td colspan="2"> 1240,15</td><td colspan="3">(7) A3</td>

<td>Z</td><td colspan="5"> 1</td>

<img file="MX348290B_D0065.tif" />

105

Βντπτυτυ

<td>Density (calculated)</td><td>1.308 mg / m³</td>

<td>Coefficient absorption</td><td>0.726 mm^-1</td>

<td>Wavelength</td><td>1.54178 Á</td>

<td>F (000)</td><td> 518</td>

or (d) their combinations.

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

In some embodiments, Form F has an X-ray powder diffraction pattern (XRPD) essentially the same as illustrated in Fig. 16. In some embodiments, Form F has an X-ray powder diffraction pattern (XRPD). with characteristic peaks at 6,210.1 ° 2-Theta, 10.1 + 0.1 ° 2-Theta, 17.610.1 ° 2-Theta, 18.6 + 0.1 ° 2-Theta, 20.0 ± 0, l ° 2-Theta,

20,410.1 ° 2-Theta, 20,710.1 ° 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

106

29.7 ± 0.1 ° 2-Theta.

In some modalities

<img file="MX348290B_D0066.tif" />

Form F has unit cell parameters essentially equal to the following at 100 (2) K:

<td>System crystalline</td><td colspan="5">Triclinic</td>

<td rowspan="3">Space group</td><td rowspan="3">P1</td><td>to</td><td>9.6332 (3) TO</td><td> □</td><td> 105,762(3)⁰</td>

<td>b</td><td>9.7536 (4) TO</td><td> □</td><td> 95,132 (2) °</td>

<td>c</td><td>15.0592 (4) 0 TO</td><td> □</td><td> 111,332(3)°</td>

<td>V</td><td colspan="5">1240.15 (7) Á³</td>

<td>Z</td><td colspan="5"> 1</td>

<td>Density (calculated)</td><td colspan="5">1.308 mg / m³</td>

<td>Coefficient absorption</td><td colspan="5">0.726 mm^-1</td>

<td>Wavelength</td><td colspan="5">1.54178 Á</td>

<td>F (000)</td><td colspan="5"> 518</td>

In some embodiments, Form F is made from methane!

In some embodiments, Form F is solvated.

In

<img file="MX348290B_D0067.tif" />

107 some modalities

IMPI ^IWrS7 '?' L «ICAN ^wu.'SONEo_AnINDUSTRIAL Form F is solvated with methanol.

Preparation of Crystalline Forms

In some embodiments, the crystalline forms of 1 ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4—

d] pyrimidin-l-yl) piperidin-l-yl) prop-2-en-l-one are prepared as described in the Examples. It should be noted that solvents, temperatures, and other reaction conditions presented herein may vary.

Suitable Solvents

Therapeutic agents to be administered to mammals, such as humans, must be prepared according to regulatory guidelines. These government-regulated guidelines are called Good Manufacturing Practice (GMP). GMP guidelines describe acceptable levels of contamination from active therapeutic agents, such as, for example, the amount of residual solvent. in the final product. Preferred solvents are those that are suitable for use in GMP facilities and that are consistent with industrial safety concerns. The categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for the Registration of Drugs for Human Use (ICH), Impurities: Guidelines

<img file="MX348290B_D0068.tif" />

<img file="MX348290B_D0069.tif" />

for Residual Solvents, Q3C (R3), (novi embre, 2005).

Solvents are classified into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents of limited use during the manufacture of the therapeutic agent. Class 3 solvents are solvents with low toxic potential and less risk to human health. Data for class 3 solvents indicate 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-dichloroethene; and 1,1,1-trichloroethane.

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

Class 3 solvents, which have low toxicity, include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), eumene, dimethyl sulfoxide, ethanol, ethyl acetate, ether

109

<img file="MX348290B_D0070.tif" />

MEXICAN INSTITUTE.

C'E LA Pk PlkOAü INDUSTRIAL ethyl, ethyl formate, formic acid, hept áYnTr ~ crre. fe to isobutyl, isopropyl acetate, methyl acetate, 3-methyl-1-bütanol, methylethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of the API. In some cases, the solvents are not completely removed by practical manufacturing techniques. Proper solvent selection for synthesis of APIs can improve yield, or can determine characteristics such as crystalline form, purity, and solubility. Therefore, the solvent is a critical parameter in the synthesis process.

In some embodiments, the compositions that Compound 1 includes include one or more organic solvents. In some embodiments, compositions that include Compound 1 include a residual amount of one or more organic solvents. In some embodiments, compositions that include Compound 1 include a residual amount of a class 3 solvent. In some embodiments, the organic solvent is a class 3 solvent. In some embodiments, the class 3 solvent is selected to

<img file="MX348290B_D0071.tif" />

start from the group that

110 consists in

IMPI

INSTITUTO MIXICAN OS LA AkOHEDAU INC USTWIAL acetic acid, acetone anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, eumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid , heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methylethyl ketone, methyl isobutyl ketone, 2-methyl-l-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrof, uranus. In some embodiments, the class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

Certain Terminology

Unless otherwise defined, all technical and scientific terms used herein have the same meaning usually known to those of skill in the art to which the claimed subject matter belongs. It will be understood that the foregoing general description and the following detailed description are merely illustrative and explanatory and do not limit the claimed subject matter. In the present application, the use of the singular includes the plural, unless otherwise specifically indicated. It should be noted that, as used in the specification and appended claims, the singular forms a, an, and the include the

<img file="MX348290B_D0072.tif" />

111

LMPI heard the plural referents, unless the context stipulates something different. In the present application, "us" means and / or, unless otherwise indicated.

Furthermore, the use of the term including, as well as in other ways, such as include, includes, and included, is not exhaustive.

The section titles used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application, which, but is not limited to, include patents, patent applications, articles, texts, manuals, and essays, are expressly incorporated by reference in their entirety for all the weekends.

As used herein, the term acceptable or pharmaceutically acceptable, with respect to a formulation, composition or ingredient, means that it lacks any persistent deleterious effect on the general health of the subject being treated or does not abrogate the biological or the properties of the compound, and that it is relatively non-toxic.

As used herein, the term "agonist" refers to a compound, the presence of which results in a biological activity of a protein that is equal to the

<img file="MX348290B_D0073.tif" />

. 112 biological activity product of the presence of natural protein, such as, for example, Btk; ---— · -

As used herein, the term "partial agonist" refers to a compound whose presence results in a biological activity of a protein that is of the same type as that resulting from the presence of a natural ligand for the protein, but less magnitude.

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

As used herein, amelioration of the symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to lessening of severity, delaying onset, delaying of advance, or decrease in duration, whether permanent or temporary, persistent or transitory, that can be attributed to or associated with the administration of the compound or composition.

Η3 Mexican iNSTmrru

Bioavailability refers to the percentage? FtíC5 ^^ * "d ^ * w? ^ X Compound 1 administered that enters the general cirra ^^ iAn · of the animal or human being studied. The total exposure (AUC (or—)) of a drug when administered intravenously is usually defined as 100% bioavailable (F%). Oral bioavailability refers to the degree to which Compound 1 is absorbed into the general circulation when the. Pharmaceutical composition is administered orally compared to an intravenous injection.

Blood 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 considerably between subjects, due to its variability with respect to metabolism and / or its possible interactions with other therapeutic agents. In accordance with one embodiment described herein, the blood plasma concentration of Compound 1 can vary from subject to subject. Also, values ​​such as maximum plasma concentration (C_max) or time to reach maximum plasma concentration (T_max), or total area under the plasma concentration time curve (AUC (o- ~>) can vary from one subject to another. Due to this variability, the amount necessary to constitute a therapeutically effective amount of Compound 1 can

<img file="MX348290B_D0074.tif" />

114 vary from one subject to another.

IMPI

MEXICAN INSTITUTE

I HEARD LA WOMEDAO INDUSTRIAL

As used herein, the term Bruton's tyrosine kinase refers to the Bruton's tyrosine kinase from Homo sapiens, described in, for example, US Pat.

US No. 6,326,469 (GenBank Accession No. NP 000052).

As used herein, the term "Bruton's tyrosine kinase homologue" refers to the Bruton tyrosine kinase orthologs, for example, mouse (GenBank Accession No. AAB47246), dog (GenBank Accession No. GenBank Accession XP_549139.), Rat (GenBank Accession No. NP_001007799), chicken (GenBank Accession No. NP_989564), or zebrafish (No. GenBank Accession XP_698117), and to the fusion proteins of any of the above that exhibit kinase activity toward one or more Bruton tyrosine kinase substrates (eg, a peptide substrate having the amino acid sequence AVLESEEELYSSARQ).

As used herein, the terms co-administration or the like are intended to encompass administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or a different route of administration. either simultaneously or at a different time.

¹¹⁵ JMPls

As used herein, the term "industrial effective ST ^ S ^^" or therapeutically effective amount refers to a sufficient amount of an agent or compound that is administered that will alleviate to some degree one or more of the symptoms of the disease or condition. that is being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, a therapeutically effective amount is that amount of the composition including a compound described herein necessary to achieve a clinically significant decrease in symptoms of the disease without undue adverse side effects. An effective amount appropriate in any individual case can be determined using techniques, such as a dose escalation study. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An effective amount of a compound described herein is an amount effective to achieve a desired pharmacological effect or therapeutic improvement, without undue adverse side effects. It is understood that an effective amount or a therapeutically effective amount may vary from subject to subject, due to variation in Compound 1 metabolism, age, weight, condition.

<img file="MX348290B_D0075.tif" />

₁₁₆ IMPI

INSTITUTO MEXICANA,,, Df THE general CURRENCY of the subject, the condition being treated, the degree of the condition being treated, and the criterion of the treating physician. By way of example only, therapeutically effective amounts can be determined by routine experimentation, which but does not include a dose escalation clinical experiment.

The terms "potentiate" or "potentiating" mean to increase or prolong a desired effect, either in potency or duration. By way of example, potentiating the effect of therapeutic agents refers to the ability to increase or prolong, either in potency or in duration, the effect of therapeutic agents during the treatment of a disease, disorder or condition. As used herein, an "effective enhancing amount" refers to an amount suitable to enhance the effect of a therapeutic agent in the treatment of a disease, disorder, or condition. When used in a patient, effective amounts for this purpose depend on the severity and progression of the disease, disorder, or condition, previous therapy, the patient's health and response to drugs, and judgment. of the treating physician.

As used herein, the term "homologous cysteine" refers to a cysteine ​​residue that is located at a position in the sequence that is homologous to that of the IMPI ir

INSTITUTO MEXICANO cysteine ​​481 of Bruton's tyrosine kinase, comd 'in the present For example, cysteine ​​482 i * cysteine ​​homologous to the rat ortholog of Bruton's tyrosine kinase; cysteine ​​479 is the homologous cysteine ​​of chicken ortholog; and cysteine ​​481 is the homologous cysteine ​​in the zebrafish ortholog. In another example, the homologous cysteine ​​of TXK, a member of the Tec kinase family related to Bruton's tyrosine, is Cys 350. Other examples of kinases that have homologous cisternae are shown in 1. See also the tyrosine kinase (TK) sequence alignments posted on the Internet at kinase.com/human/kinome/phylogeny.html.

As used herein, the term "identical" refers to two or more sequences or subsequences that are the same. Furthermore, as used herein, the term "essentially identical" refers to two or more sequences that have the same percentage of sequential units when compared and aligned to achieve maximum correspondence in a comparison window, or in a certain region that it is measured using comparison algorithms or by manual alignment and visual inspection. By way of example only, two or more sequences can be essentially identical if the sequential units are about 60% identical, about 65% identical, about 70% identical about 7

CH THE INDUSTRIAL PROPERTY around 80% identical, around 85% identical, around 90% identical, or around 95% identical in a specific region. These percentages describe the percent identity of two or more sequences. The identity of a sequence can exist in a region with a length of at least about 75-100 sequence units, in a region with a length of about 50 sequence units, or, where not specified, throughout the entirety of sequence. This definition also refers to the complement of an experimental sequence. By way of example only, two or more polypeptide sequences are identical when the amino acid residues are the same, while two or more polypeptide sequences are essentially identical if the amino acid residues are about 60% identical, about 65% identical. , around 70% identical, around 75% identical, around 80% identical, around 85% identical, around 90% identical, or around 95% identical in a specific region. Identity can exist in a region that is at least about 75-100 amino acids long, in a region that is about 50 amino acids long, or, where not specified, throughout the entire sequence of a sequence. of polypeptides.

IM PIíc ¹¹⁹ ”™ Ss:« s

Also, by way of example only, two or more polynucleotide sequences * are identical when the nucleic acid residues are the same, while two or more polynucleotide sequences are essentially identical if the nucleic acid residues are about 60% identical. , around 65% identical, around 70% identical, around 75% identical, around 80% identical, around 85% identical, around 90% identical, or about 95% identical in a specific region. Identity may exist in a region with a length of at least about 75-100 nucleic acids, in a region with a length of about 50 nucleic acids, or, where not specified, throughout the entire sequence of a sequence of polynucleotides.

As used herein, the terms "inhibit, inhibit, or inhibit a kinase" refer to the inhibition of enzymatic phosphotransferase activity.

As used herein, the term "irreversible inhibitor" refers to a compound that, upon contact with a target protein (eg, a kinase), causes the formation of a new covalent bond with or in the protein and therefore , decreases or suppresses one or more of the biological activities of the target protein (e.g., phosphotransferase activity) despite subsequent _ IMPI ^

120 MEXICAN INSTITUTE

OF THE INDUSTRIAL l> »OII £ DAL O ··» presence or absence of the irreversible inhibitor.

As used herein, the term "irreversible inhibitor of Btk" refers to an inhibitor of Btk that can form a covalent bond with an amino acid residue of Btk. In one embodiment, the irreversible inhibitor of Btk can form a covalent bond with a Cys residue of Btk; In particular embodiments, the irreversible inhibitor can form a covalent bond with a Cys 481 residue (or one of its homologues) of Btk or with a cysteine ​​residue in the homologue that corresponds to the position of another tyrosine kinase.

As used herein, the term "isolated" refers to separating and removing a component of interest from components that lack interest. The isolated substances can be in the dry or semi-dry state, or in solution, which but does not include an aqueous solution. The isolated component may be in a homogeneous state or the isolated component may form part of a pharmaceutical composition that includes other pharmaceutically acceptable carriers and / or excipients. By way of example only, nucleic acids or proteins are isolated when these nucleic acids or proteins are free of at least some of the cellular components with which they naturally associate, or when the nucleic acid or protein is concentrated.

121 protein at a level higher than in vivo or in vitro production. Further,

<img file="MX348290B_D0076.tif" />

<img file="MX348290B_D0077.tif" />

by way of example, a gene is isolated when it is separated from the open reading frames that flank the gene and that encode a protein other than the gene of interest.

As used herein, the term "modulate" means to interact with a target, either directly or indirectly, in such a way as to modify the activity of the target, which by way of example only includes enhancing the activity of the target, inhibiting the target activity, limit the activity of the target, or prolong the activity of the target.

As used herein, the term "modulator" refers to a compound that modifies an activity of a molecule. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In

122

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. . -. ,, -. .,, _, Dt LA PRJrltuAv certain modalities, the presence of a modulator has ^^ Wtno result an activity that does not occur in the auranciu dUT modulator.

As used herein, the term "prophylactically effective amount" refers to that amount of a composition that is applied to a patient that mitigates to some degree one or more of the symptoms of a disease, condition, or disorder being treated. In some prophylactic applications, these amounts depend on the patient's health status, weight, and the like. Determination of prophylactically effective amounts by routine experimentation is believed to be within the skill of the art, which does not include a dose escalation clinical experiment.

As used herein, the term "subject" refers to an animal that undergoes treatment, observation, or experimentation. By way of example only, a subject may non-exhaustively be a mammal, which non-exhaustively includes a human.

As used herein, the term "target activity" refers to a biological activity capable of being modulated with a selective modulator. Some examples of non-limiting target activities include binding affinity, signal transduction, enzymatic activity,

123 IMPI ^ ^INST™ T ”MEXICAN

Ί · · 4- J 4- Ί _£1 ^ LArKOWElAL · the growth of tumors, the inflammatory processes associated with inflammation, and the improvement of one more jíntomm, ___ associated with a disease or condition.

As used herein, the term "target protein" refers to a molecule or portion of a protein capable of binding to a selectively binding compound. In certain embodiments, a target protein is Btk.

As used herein, the terms treat, treating, or treating include the alleviation, amelioration, or amelioration of the symptoms of a disease or condition, the prevention of additional symptoms, the amelioration or prevention of the underlying metabolic causes of the symptoms, the inhibition of the disease or condition, for example, by stopping the progression of the disease or condition, alleviation of the disease or condition, regression of the disease or condition, alleviation of a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms "treat", "treating" or "treatment" are not limited to include prophylactic and / or therapeutic treatments.

As used herein, IC₅₀ refers to an amount, concentration, or dose of a particular experimental compound that achieves 50% inhibition of a maximal response, such as inhibition of Btk, in an assay that measures

124 This answer.

IMPI i / vjrrrnrroM «icAN.

oí u nontt AD INDUSTRIAL

<img file="MX348290B_D0079.tif" />

As used herein, EC₅or se · * ·· ^ ί ~^Ί~^ο at a dose, concentration, or amount of a particular experimental compound that produces a dose-dependent response to 50% of the maximal expression of a particular response that is induced, elicited, or potentiated with that particular experimental compound.

Pharmaceutical Compositions / Formulations

Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate processing of the active compounds into pharmaceutically usable preparations. A suitable formulation depends on the chosen route of administration. Any of the widely known techniques, carriers, and excipients appropriate and known in the art can be used. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,

Pennsylvania 1975; Liberman, HA and Lachman, L., Eds.,

Pharmaceutical Dosage Forms, Marcel Decker, New York, NY,

<img file="MX348290B_D0080.tif" />

1980; and Pharmaceutical Dosage Forms and-. Drug Delivery Systems, Seventh Edition (Lippincott Williams &amp; Wilkins 1999), which are incorporated herein by reference in their entirety.

As used herein, a pharmaceutical composition refers to a mixture of Compound 1 with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, binding agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to a mammal. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of Compound 1 in a pharmaceutical composition are administered to a mammal suffering from a disease, disorder, or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount may vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds can be used individually or in combination with one or more therapeutic agents as components of the mixtures.

As used herein, the term "pharmaceutical combination" means a product that is the result of ¹²⁶ LM P í ^{, Ν}* ΤΓΠ 'ΤΟ MEXICAN uiiii

-,,. /,. ,,,,, OF THE CURRENCY> «5 J mixing or combining more than one active ingredient and inwwjnyei both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example Compound 1 and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dose. The term non-fixed combination means that the active ingredients, for example Compound 1 and a co-agent, are administered to a patient in the form of independent entities either simultaneously, concomitantly or sequentially, without interposition of specific time limits, where the Administration achieves effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example the administration of three or more active ingredients.

In some embodiments, crystalline Compound 1 is incorporated into pharmaceutical compositions to obtain solid oral administration forms. In other embodiments, crystalline Compound 1 is used to prepare different pharmaceutical compositions of solid oral administration forms. The pharmaceutical formulations described herein can be administered to a subject by multiple routes of administration, including but not limited to, oral, parenteral (e.g., intravenous,

127 Unholy ^{± ζ}· 'ΊΝΓπτυτυ mexjcan

DB LA FIORÍtAD subcutaneous, intramuscular), intranasal, buccal, ^{, ndu}T ^ íc ^ trectal, or transdermal. The pharmaceutical formulations described but not limited to herein include aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid administration forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets. , capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and immediate and controlled release mixed formulations.

Compositions including a compound described herein can be made in a conventional manner, such as, by way of example only, by conventional processes of combining, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, entrapment, or compression.

Dosage Forms

The pharmaceutical compositions described herein may be formulated for administration to a mammal by any conventional means, including but not limited to, oral, parenteral (eg,

128 IMPI ^ g

INSTITUTO MUICAN · example, intravenous, subcutaneous, or intramuscuí »iR ^ A * bSBK ^^ 'intranasal, rectal or transdermal. As presently, the term subject is used to refer to an animal, preferably a mammal, including a human or non-human. The terms patient and subject can be used interchangeably.

In addition, the pharmaceutical compositions described herein, which include Compound 1, can be formulated in a suitable administration form, including but not limited to, solid oral administration forms, controlled release formulations, fast melt formulations, formulations. effervescent, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

Pharmaceutical preparations for oral use can be obtained by combining one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if required. desired, to obtain tablets or dragee cores. Excipients that can be used, for example, include₁₂₉ ΙΜΡΙ £ tNSTHlITO MEXICAN

FROM THE MRNEDAÍ V * fillers such as sugars, what lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents can be added, such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or algic acid or a salt thereof such as sodium alginate.

Pharmaceutical preparations that can be used orally include hard capsules made from gelatin, as well as soft, sealed capsules made from gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules can contain the active ingredients in combination with a filler material such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizing agents. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizing agents can be added. All formulations for oral administration must meet 'iW'¹ in dosage forms suitable for this administration.

In some embodiments, the solid forms of administration described herein may take the form of a tablet, (including a suspension tablet, a fast melt tablet, a disintegrating tablet on consumption, a fast disintegration tablet, an effervescent tablet, or a tablet), a pill, a powder (which includes a sterile packed powder, a dispensed powder, or an effervescent powder), a capsule (which includes soft or hard capsules, e.g. capsules made from HPMC gelatin of animal or plant origin, or sprinkle capsules), a solid dispersion, a solid solution, a biodegradable administration form, controlled release formulations, release administration forms pulsatile, multiparticulate administration forms, tablets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation takes the form of a powder. In still other embodiments, the pharmaceutical formulation takes the form of a tablet, including but not limited to, a fast melt tablet. Additionally, the pharmaceutical formulations described herein can be administered in the form of a single capsule or in the form of multiple¹³¹ IMPI capsules. In some embodiments, the INDUSTRIAL formulation - is administered in two, or three, or four, capsules or tablets. __.

In some embodiments, solid forms of administration, eg, tablets, effervescent tablets, and capsules, are prepared by combining Compound 1 particles with one or more pharmaceutical excipients to obtain an unprocessed mixed composition. When these unprocessed mixed compositions are referred to as homogeneous, it means that the Compound 1 particles are uniformly dispersed in the composition such that the composition can be easily subdivided into equally effective dosage unit forms such as tablets, pills, and capsules. Individual unit doses may also include film-like coatings, which disintegrate after oral ingestion or on contact with diluent. These formulations can be made by conventional pharmacological techniques.

Conventional pharmacological techniques include, for example, one or a combination of the methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation , or (6) merger. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, coating on

132 IMPI ^ ^iJZ INSTITUTE .MLXICak

M LA MOM! Í> ad ióC3e hype, melt granulation, granulation, secaS # o - ^ - fluid bed spray coating (eg, wurster coating), tangential coating, top spray, tabletting, extrusion and the like .

The solid forms of pharmaceutical administration described herein can include Compound 1 and one or more pharmaceutically acceptable additives such as a compatible carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetening agent, a disintegrating agent, a dispersing agent, a surfactant, a lubricant, a colorant, a diluent, a solubilizing agent, a wetting agent, a plasticizer, a stabilizing agent, a penetration enhancer, a wetting agent, an anti-foaming agent, an antioxidant, a preservative, or one or more combinations thereof. In still other aspects, conventional coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), are used to form a film of a shell around the formulation of Compound 1. In one embodiment, some or all of the Compound 1 particles. In another embodiment, some or all of the Compound 1 particles are microencapsulated. In yet another embodiment, they are neither microencapsulated nor

133

INSTITUTE MtXICAN the particles of T

1.

Suitable carriers that can be used in the solid forms of administration described herein but not limited to include acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate. , soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, Hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.

Suitable fillers that can be used in the solid forms of administration described herein but not limited to include lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

<img file="MX348290B_D0081.tif" />

IMPI medican institute

In order to release Compound 1 from the matrix of a solid administration form as efficiently as possible, disintegrators are often used in the formulation, especially when the administration forms are compressed with a binder. Disintegrators help to fracture the matrix of the administration form by dilatation or capillary action, when moisture is absorbed in the administration form. Suitable disintegrators that can be used in the solid administration forms described herein but not limited to include a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or a glycolate of sodium starch such as Promogel® or Explotab®, a cellulose such as a wood product, a crystalline methylcellulose, for example Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® PIDO, Emcocel®, Vivacel®, Ming Tía®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol®), cross-linked carboxymethyl cellulose, or cross-linked croscarmellose, a cross-linked starch such as glycolate sodium starch, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, an alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV

135 IMPI ^ instituto mixicanci (magnesium aluminum silicate), a gum such guar, carob, karaya, pectin, or tranaranta ,. Hp sodium starch, bentonite, a natural sponge, a surfactant, a resin such as a cation exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like. In some embodiments provided herein, the disintegrating agent is selected from the group consisting of a natural starch, a pregelatinized starch, a sodium starch, crystalline methyl cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose, reticulated carboxymethyl cellulose cross-linked, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, or a gum. In some embodiments provided herein, the disintegrating agent is croscarmellose sodium.

Binders impart cohesion to formulations of solid oral forms of administration: in the formulation of a capsule filled with powder, they help to form a plug that can be inserted into soft or rigid capsules and, in the formulation of tablets, they ensure They keep the tablet intact after compression and help to ensure uniformity of the mix prior to a compression or filling step. Materials suitable for use as binders in the solid administration forms described herein but not limited to include carboxymethylcellulose, methylcellulose (e.g. Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, Hydroxypropylmethylcellulose acetate stearate ( Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (for example Klucel®), ethyl cellulose (for example Ethocel®), and microcrystalline cellulose (for example, Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, dextrinized, tragatrin a sugar, such as sucrose (eg Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (eg Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, isapol husk mucilage, starch, polyvinylpyrrolidone (for example, Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, waxes, alginate sodium, and the like.

In general, levels of the 20137 IMPI binder are used ^

MEXICAN INSTITUTE

70% in powdered gelatin capsule formulations. The level of use of the binder in tablet fomnilarinnac ·, - varies depending on whether direct compression, wet granulation, roller compaction, or other excipients such as fillers are used that themselves can behave as a mild binder. Formulators of skill in the art can determine the level of binder in formulations, but a level of binder use of up to 70% is common in tablet formulations.

The lubricants or glidants that can be used in the solid forms of administration described herein but not limited to include stearic acid, calcium hydroxide, talc, cornstarch, sodium stearyl fumarate, the alkali metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol, or a methoxy polyethylene glycol such as Carbowax ™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate , and the like. In some modalities provided herein, the

<img file="MX348290B_D0082.tif" />

138

IMPI hear the Motion _TONOUSTRJaI lubricant is selected to stearic acid, hydroxide from the group consisting of calcium, talc, cornstarch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments provided herein, the lubricant is magnesium stearate.

Suitable diluents that can be used in the solid forms of administration described herein but not limited to include sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like. In some embodiments provided herein, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

The term water-insoluble diluent represents the compounds typically used in drug formulation, such as calcium phosphate, calcium sulfate, starches, modified starches, and microcrystalline cellulose.

<img file="MX348290B_D0083.tif" />

and microcellulose

IMPI Mexican institute DE LA FRONEDAL

INDUSTRIAL

139 (for example, with a density of around 0.45 g / cm³, for example, Avicel, powdered cellulose), and talc.

Suitable wetting agents that can be used in the solid dosage forms described herein, for example, include oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene monolaurate. sorbitan, quaternary ammonium compounds (e.g. Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, docusate sodium, triacetin, vitamin E TPGS and the like. '

Suitable surfactants that can be used in the solid administration forms described herein, for example, include sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, oxide copolymers of ethylene and propylene oxide, eg Pluronic® (BASF), and the like. In some embodiments provided herein, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, salts ₁₄₀ IMPI ^

0 iNsrmm> mexican ψζ- * ·

DE LA PROREDAΓ V ** ·

INDUSTRIAL bile, glyceryl monostearate, ethylene oxide and propylene oxide copolymers. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

Suitable suspending agents that. can be used in the solid forms of administration described herein but not limited to include polyvinylpyrrolidone, for example, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, for example, polyethylene glycol may have about a molecular weight 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,. polysorbate-80, hydroxyethyl cellulose, sodium alginate, gums, such as, for example, gum tragacanth and gum acacia, guar gum, xanthanes, including xanthan gum, sugars, cellulosic agents, such as, for example, sodium carboxymethyl cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

INSTITUTO MEXICANO Dt LA FAOHÍL AD INDUSTRIAL

Suitable antioxidants that can be used in the solid administration forms described herein, for example, include butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

It will be appreciated that there is considerable overlap between the additives used in the solid dosage forms described herein. Accordingly, the above-listed additives are to be considered merely illustrative, and not limiting, of the types of additives that can be included in the solid dosage forms described herein. The amounts of these additives can be readily determined by those skilled in the art, according to the particular properties desired.

In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, a plasticizer is generally a high-boiling solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Non-limiting plasticizers include diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol,

<img file="MX348290B_D0084.tif" />

142 stearate, and castor oil.

Compressed tablets are icy administration tablets prepared by compacting the crude mixture of the formulations described above. In various embodiments, compressed tablets that are designed to dissolve in the mouth include one or more flavoring agents. In other embodiments, the compressed tablets include a film that surrounds the final compressed tablet. In some embodiments, coating in the form of a film can achieve sustained release of Compound 1 from the formulation. In other embodiments, the coating in the form of a film contributes to patient satisfaction (eg, Opadry® covers or sugar coating). Coatings in the form of films that include Opadry® typically range from about 1% to about 3% of the weight of the tablet. In other embodiments, the compressed tablets include one or more excipients.

A capsule can be prepared, for example, by placing the raw mix of the Compound 1 formulation inside a capsule. In some embodiments, the formulations (suspensions and non-aqueous solutions) are placed in a soft gelatin capsule. In other embodiments, the formulations are placed in conventional gelatin capsules or in different gelatin capsules such as

IMPI

3 iNSTtniro MWicxN.

FROM THE EROME DAD 'NDUSTRIAL capsules that include HPMC. In other embodiments, formulation is placed in a rigid capsule, where the capsule can be swallowed whole or the capsule can be opened and can be

<img file="MX348290B_D0085.tif" />

sprinkle the content on food before consuming it.

In some embodiments, the therapeutic dose is divided into multiple (eg, two, three, or four) capsules. In some embodiments, the entire dose of the formulation is administered in the form of a capsule.

In various embodiments, the particles of Compound 1 and one or more excipients are dry-blended and compressed into a mass, such as a tablet, that has a sufficient hardness to provide a pharmaceutical composition that essentially disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after its oral administration and that, therefore, releases the formulation in the gastrointestinal fluid.

In another aspect, the administration forms can include microencapsulated formulations. In some embodiments, there are one or more different compatible materials present in the microencapsulation material. Some examples of non-exhaustive materials include

IMPI fNrrrnrro mexican 144 “UrtOEtDAt

INDUSTRIAL pH modifiers, erosion promoters, antifoaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrating agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

Materials useful in the microencapsulation described herein include materials compatible with Compound 1 that sufficiently isolate Compound 1 from the others. incompatible excipients. Materials compatible with Compound 1 are those that delay the release of Compound 1 compounds in vivo.

Some examples of microencapsulation materials

<img file="MX348290B_D0086.tif" />

useful for delaying the release of formulations that include the compounds described herein, but not limited to, include hydroxypropyl cellulose (HPC) ethers such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L- HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, Primario, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metolose®, Ethylcelluloses (EC) and their combinations such

IMPI »5

INSTITUTO MEXIGAN · DE LA PROPIE PA I * 14 $ industrial as E4 61, Ethocel®, Agualon®-EC, Surelease®, —ua — Al ^ hol. ___ polyvinyl (PVA) such as Opadry AMB, hydroxyethyl celluloses such as Natrosol®, carboxymethyl celluloses and carboxymethyl celluloses (CMC) salts such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol copolymers such as Kollicoat IR®, monverogollycol ), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and blends of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® SIDO, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, Phthalate Acetate of cellulose, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols, eg, PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulation material useful for delaying the release of pharmaceutical compositions is from the USP or the National Formulary (NF). In even other modalities

<img file="MX348290B_D0087.tif" />

146

IMPI

INSTITUTE MtJUCAM DI LA IkOPILOAL INDUSTRIAL the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is methocel.

Microencapsulated Compound 1 can be formulated by methods known to those of ordinary skill in the art. These known methods include, for example, spray drying processes, solvent-rotary disk processes, hot melt processes, spray cooling methods, electrostatic fluid bed deposition, centrifugal extrusion, separation by rotational suspension, polymerization at the liquid-gas or solid-gas interface, extrusion under pressure, or the spray solvent extraction bath. In addition to these, various chemical techniques can also be used, for example, complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid medium, polymerization in situ, drying in liquid, and desolvation in liquid medium. In addition, other methods such as roller compaction, extrusion / spheronization, coacervation, or nanoparticle coating can also be used.

In one embodiment, the Compound 1 particles are microencapsulated prior to formulating them in one of the foregoing ways. In still another embodiment, some or

147

<img file="MX348290B_D0088.tif" />

IMPI the majority of the particles before formulatingl ^ ñ ^^^^ g ^^ 'ndustÍ'ial using traditional coating procedures, such as those described in

Remington's Pharmaceutical

Sciences, 20th Edition (2000).

In other embodiments, the solid delivery formulations of Compound 1 are plasticized (coated) with one or more layers. Illustratively, a plasticizer is generally a high melting point solid or liquid.

Suitable plasticizers can be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Non-limiting plasticizers include diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

In other embodiments, a powder including the formulations with Compound 1 can be formulated to include one or more pharmaceutical excipients and flavors. This powder can be prepared, for example, by combining the formulation and optional pharmaceutical excipients to form a crude mixed composition. Other embodiments also include a suspending agent and / or a wetting agent. This raw mixture is evenly subdivided into units

IMPIAS

INSTmiTO MEXICANO '¿«g ·

DE LA CURRENCY g INDUSTRIAL single dose or multiple dose dnsj.a.

In still other embodiments, effervescent powders are also prepared in accordance with the present invention. Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are coarse granules or powders that contain a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid, and / or tartaric acid. When salts of the compositions described herein are added to water, the acids and base react to liberate carbon dioxide gas and, consequently, cause effervescence. Some examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. Any acid-base combination that results in the release of carbon dioxide can be used instead of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients are for pharmaceutical use and result in a pH of around 6.0 or higher.

In some embodiments, the solid forms of administration described herein may be formulated in the form of oral release forms of administration.

<img file="MX348290B_D0089.tif" />

149

IMPI

IHSTmjT · MEXICAN • E LA INDUSTRIAL CURRENCY enteric coated, that is, as an oral administration form of a pharmaceutical composition described herein that uses an enteric coating to effect release in the small intestine of the gastrointestinal tract. The enteric-coated administration form may be a compressed or molded or extruded (coated or uncoated) tablet / mold containing granules, powder, tablets, beads or particles of the active ingredient and / or other components of the composition, which are in themselves covered or not. The enteric-coated oral administration form can also be a capsule (coated or not) containing tablets, beads or granules of the solid carrier or composition, which are themselves coated or not.

The term "sustained release" as used herein refers to administration in such a way that release can be achieved at some generally predictable location in the intestinal tract more distal to that which would have been achieved without sustained release disturbances. In some embodiments, the method of delaying release is coating. The coatings should be applied in a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at a pH below about 5, but dissolves at a pH of about 5 and above. It is envisioned that any anionic polymer that

150 present a solubility profile

IMPI wsTnvro Mexican Dt UA PXOPIEÜAD INDUSTRIAL

<img file="MX348290B_D0090.tif" />

pH dependent as an enteric coat in the methods and compositions described herein to achieve administration to the lower gastrointestinal tract. In some embodiments, the polymers described herein are anionic carboxylic polymers. In other embodiments, the polymers and their compatible blends, and some of their properties, but not limited to include:

Lacquer, also called purified lacquer, a refined product obtained from the resinous secretion of an insect. This coating dissolves in a medium with pH> 7;

Acrylic polymers. The behavior of acrylic polymers (mainly their solubility in biological fluids) can vary based on the degree and type of substitution. Some examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit E, L, S, RL, RS and NE series (Rohm Pharma) are available dissolved in an organic solvent, or in the form of an aqueous dispersion, or as dry powders. The Eudragit RL, NE, and RS series are insoluble in the gastrointestinal tract but are permeable and are primarily used as colonic targets. The Eudragit E series dissolves in the stomach. The Eudragit L, L-30D and S series are insoluble in the

<img file="MX348290B_D0091.tif" />

151 stomach and dissolve in the intestine;

IMPI uc tA '^' US_Wai

Cellulose Derivatives. Some examples of suitable cellulose derivatives include: ethyl cellulose; the reaction mixtures of partial esters of cellulose acetate with italic anhydride. Its behavior may vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH> 6. Aquateric (EMC) is an aqueous system and is a spray dried CAP psuedolatex with particles <1 pm. Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose trimellitate acetate (Eastman); methylcellulose (Pharmacoat, Methocel);

Hydroxypropyl Methyl Cellulose Phthalate (HPMCP); Hydroxypropyl Methyl Cellulose Succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (eg, AQOAT (Shin Etsu)). Its behavior may vary depending on the degree and type of substitution. For example, HPMCP such as, grades HP-50, HP-55, HP-55S, HP-55F can be used. Its behavior may vary depending on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate but not limited to include AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at a higher pH. These polymers are offered in the form of granules, or powders

IMPI 'INSTITUTO MUUCAN · T. - _r „O» LA MOHEBa »C

152 industrial ^xfines for aqueous dispersions; Polyvinyl Phthalate Acetate (PVAP). PVAP dissolves at pH> 5, and is much less permeable to water vapor and gastric fluids.

In some embodiments, the coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and / or magnesium stearate, which are widely known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, asters fatty acids, propylene glycol, and dibutyl phthalate. In particular, anionic acrylic carboxylic polymers usually contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional coating techniques such as spray or tray coating are used to apply the covers. The thickness of the coating should be sufficient to ensure that the oral administration form remains intact until the desired site of topical delivery is reached in the intestinal tract.

Colorants, release agents, surfactants, antifoam agents, lubricants (for

<img file="MX348290B_D0092.tif" />

153

IMPI iNSTrruTi. mexican

DE LA M »F! EDAL INDUSTRIA!

eg, carnuba wax or PEG) to coatings in addition to plasticizers to solubilize or disperse the coating material, and improve the performance of the coating and the coated product.

In other embodiments, the formulations described herein, which include Compound 1, are administered using a pulsatile form of administration. A pulsatile form of administration is capable of providing one or more immediate release pulses at predetermined times in time after a controlled delay time or at specific locations. Many other types of controlled release systems known to those of ordinary skill in the art can be used with the formulations described herein. Some examples of these delivery systems include, for example, polymer-based systems, such as polylactic and polyglycolic acid, polyanhydrides, and polycaprolactone; porous matrices, systems that are not based on polymers that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel delivery systems; silastic systems; peptide-based systems; wax coatings, bioerodible forms of administration, compressed tablets that

<img file="MX348290B_D0093.tif" />

154

IMPI

INSTITUTO MíXica * j &lt;'Nt'UJTXUt use conventional binders and the like. See, for example, Liberman et al., Pharmaceutical Dosage Forms, 2 Ed.,

Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of

Pharmaceutical Technology, 2^gives Ed., Pp. 751-753 (2002); U.S. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983, each of which is specifically incorporated by reference.

In some embodiments, pharmaceutical formulations are provided that include Compound 1 particles, at least one dispersing agent, or one suspending agent for oral administration to a subject. The formulations can be a suspension powder and / or granules, and when combined with water, an essentially uniform suspension is obtained.

It will be appreciated that there is an overlap between the above-listed additives used in the aqueous dispersions or suspensions described herein, in that a given additive is often classified differently by different practitioners in the field, or is commonly used for various functions. different Accordingly, the additives listed above are to be construed as merely illustrative, and not limiting, of the types of additives that can be included in the formulations described herein. Amounts of

<img file="MX348290B_D0094.tif" />

155

IMPI

MfJdCAN INSTITUTE

THE INDUSTRIAL PROPERTY these additives can easily be determined by those skilled in the art, according to the particular properties desired.

Dosage and Treatment Regimens

In some embodiments, the amount of Compound 1 that is administered to a mammal is 300 mg / day up to and including 1000 mg / day. In some embodiments, the amount of Compound 1 that is administered to a mammal is 420 mg / day up to and including 840 mg / day. In some embodiments, the amount of Compound 1 that is administered to a mammal is about 420 mg / day, about 560 mg / day, or about 840 mg / day. In some embodiments, the amount of Compound 1 that is administered to a mammal is about 420 mg / day. In some embodiments, the amount of Compound 1 that is administered to a mammal is about 560 mg / day. In some modalities, the AUC₀-24 of Compound 1 is between about 150 and about 3500 ng * h / mL. In some modalities, the AUC_OR-24 of Compound 1 is between about 500 and about 1100 ng * h / mL. In some embodiments, Compound 1 is administered orally. In some embodiments, Compound 1 is administered once a day, twice a day, or three times a day. In some embodiments, Compound 1 is administered daily. In some modalities, Compound 1

IMPI

156

INSTITUTO MIXICAN OS LA ΜοΡΙΕΟλΓ INDUSTRIAL is administered once a day. In some modalities the

Compound 1 is administered every other day. In some embodiments, Compound 1 is a maintenance therapy.

Compound 1 can be used in the preparation of medicaments for the inhibition of Btk or one of its homologues, or for the treatment of diseases or conditions that benefit, at least in part, from the inhibition of Btk or one of its homologues. , which includes a subject with a diagnosis of hematology malignancy. Furthermore, a method for treating any of the diseases or conditions described herein in a subject in need of this treatment involves the administration of pharmaceutical compositions containing Compound 1, or a pharmaceutically acceptable salt, a pharmaceutically acceptable Noxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

Compositions containing Compound 1 can be administered as prophylactic, therapeutic, or maintenance treatment. In some embodiments, compositions containing Compound 1 are administered in therapeutic applications (for example, administered to a subject with a

<img file="MX348290B_D0095.tif" />

157 n * STmrro Mexican

OF THE INDUSTRIAL PROPERTY diagnosis of a hematological malignancy). In some embodiments, compositions containing Compound 1 are administered in therapeutic applications (eg, administered to a subject susceptible to or at risk of developing a hematological malignancy). In some embodiments, compositions containing Compound 1 are administered to a patient in remission as a maintenance therapy.

The amounts of Compound 1 depend on use (eg, therapeutic, prophylactic, or maintenance). The amounts of Compound 1 depend on the severity and progression of the disease or condition, previous therapy, the patient's health status, weight, and response to drugs, and the judgment of the treating physician. Determination of these therapeutically effective amounts by routine experimentation (including, but not limited to, a dose escalation clinical experiment) is believed to be within the skill of the art. In some embodiments, the amount of Compound 1 is 300 mg / day up to and including 1000 mg / day. In some embodiments, the amount of Compound 1 is 420 mg / day up to and including 840 mg / day. In some embodiments, the amount of Compound 1 is 400 mg / day up to and including 860 mg / day. In some embodiments, the amount of Compound 1 is around ± 30 and 'MU ¡CAN · t'.

OF THE P «OPl £ r_AD INDUSTRIAL VAjjT

360 mg / day. In some embodiments, the amount of Compound 1 is about 420 mg / day. In some embodiments, the amount of Compound 1 is about 560 mg / day. In some embodiments, the amount of Compound 1 is about 840 mg / day. In some embodiments, the amount of Compound 1 is from 2 mg / kg / day up to and including 13 mg / kg / day. In some embodiments, the amount of Compound 1 is 2.5 mg / kg / day up to and including 8 mg / kg / day. In some embodiments, the amount of Compound 1 is 2.5 mg / kg / day up to and including 6 mg / kg / day. In some embodiments, the amount of Compound 1 is 2.5 mg / kg / day up to and including 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 8-15 mg / kg / day.

In some embodiments, the pharmaceutical compositions described herein include about 140 mg of Compound 1. In some embodiments, a capsule formulation is prepared that includes about 140 mg of Compound 1. In some embodiments, 2 are administered, 3, 4, or 5 of the capsule formulations daily. In some modalities, 3-4 capsules are administered daily. In some modalities, 3 capsules of 140 mg are administered once a day.

In some modalities, 4 ₁₅₉ IMPI ^

INSTITUTE MtXICAN% Cltiil '

DE LA PkUriEDAD 140 mg capsules once a day. In some modes, the capsules are given once a day, they will say ---- In some modes, the capsules are given several times a 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 a day. In some embodiments, Compound 1 is administered twice daily. In some embodiments, Compound 1 is administered three times a day. In some embodiments, Compound 1 is administered four times a day.

In some embodiments, Compound 1 is administered until disease progresses, unacceptable toxicity is reached, or by individual choice. In some embodiments, Compound 1 is administered daily until disease progresses, unacceptable toxicity is reached, or by individual choice. In some embodiments, Compound 1 is administered every other day until disease progresses, unacceptable toxicity is reached, or by individual choice.

In the case where the patient's condition does not improve, at the discretion of the physician, the administration of the compounds may be continuous; alternatively, the dose of the drug

160

IMPJ ^ • LSTITUTI MEXICANO,. . ,,,. ,,. DITANOPICDAl oZ * 5S * administered can be temporarily reduced or suSgfewⁱ®erS €!^l!? _! Í temporarily during a certain period of dé tluiupu (oo ..... say, a break from the drug). The duration of the drug break can vary between 2 days and 1 year, which by way of example only includes, 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. The dose reduction during a drug break can be 10% -100%, which by way of example only includes, 10%, 15%, 20%, 25%,

30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once the improvement of the patient's conditions is achieved, a maintenance dose is administered if necessary. Subsequently, the dose or frequency of administration, or both, can be reduced as a function of symptoms, to a level at which improvement in the disease, disorder or condition is maintained. However, patients may need long-term intermittent treatment if symptoms reappear. '

The amount of a certain agent that corresponds to this amount varies depending on factors such as the particular compound, the severity of the disease, the identity (eg, weight) of the subject or host in need of treatment, but may nonetheless be determined routinely in a manner known in the art in accordance with the particular circumstances surrounding the case, including, for example, the specific agent being administered, the route of administration, and the subject or host being treated. In general, however, dosages used in treating an adult human typically range from 0.02-5000 mg per day, or about 1-1500 mg per day. The desired dose may conveniently be presented as a single dose or as divided doses administered simultaneously (or for a short period of time) or at appropriate intervals, eg, as two, three, four or more sub-doses per day.

The pharmaceutical composition described herein may be in dosage unit forms suitable for individual administration of exact dosages. In an administration unit form, the formulation is divided into doses containing appropriate amounts of one or more compounds. The unit dose can take the form of a package containing discrete amounts of the formulation. Some non-exhaustive examples include packed tablets or capsules, and powders in bottles or ampoules. Compositions in aqueous suspension can be packaged in containers not

162 Τ I

IV1 λ Α INSTITUTO MEXICANO reusable single dose. Alternatively^F,úí ^ 7rRWi^{e> 9}®2S use reusable multi-dose containers; on. which case typically a preservative is included in the composition. By way of example only, parenteral injection formulations may be presented in dosage unit form, including but not limited to ampoules, or in multidose containers, with an added preservative. In some embodiments, each dosage unit form includes 140 mg of Compound 1. In some embodiments, an individual receives 1 unit form of administration per day. In some modalities, an individual receives 2 unit forms of administration per day. In some modalities, an individual receives 3 unit forms of administration per day. In some modalities, an individual receives 4 unit forms of administration per day.

The preceding ranges are merely suggestive, in that the number of variables in relation to an individual treatment regimen is large, and substantial deviations from these recommended values ​​are not uncommon. These doses can be modified depending on numerous variables, including but not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition being treated.

<img file="MX348290B_D0096.tif" />

163

IMPI

MEXICAN INSTITUTE

DE LA ΜΟΡΙΕΙ'ΑΓ industrial treats, and the judgment of the doctor.

The toxicity and therapeutic efficacy of these therapeutic regimens can be determined by traditional pharmaceutical procedures in cell cultures or experimental animals, which but does not include the determination of LD₅q (the lethal dose for 50% of the population) and ED₅₀ (the therapeutically effective dose in 50% of the population). The dose relationship between toxic and therapeutic effects is the therapeutic index and can be expressed as the relationship between LD₅₀ and ED₅₀. Compounds exhibiting high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a variety of doses for human use. The dose of these compounds is preferably within the range of circulating concentrations that include ED₅or with minimal toxicity. The dose may vary within this range depending on the form of administration used and the route of administration used.

Combined Therapy

In certain instances, 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 conjunction with other ₁₆₄ IMPí ^

MIJíCanc INSTITUTE. Μ THE PROPERTY;

therapeutic reagents that are selected for their particular uttMacV against the condition being n'ALállclu. In general, the compositions described herein and, in the embodiments where combination therapy is used, other agents do not have to be administered in the same pharmaceutical composition and, due to different physical and chemical characteristics, are administered by different routes. In one embodiment, the initial administration is performed according to established protocols, and then, depending on the observed effects, the dose, modes of administration and times of administration are modified.

In various embodiments, the compounds are administered concomitantly (eg, simultaneously, essentially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, the condition of the patient, and the choice of compounds used. In certain embodiments, the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is based on the evaluation of the disease being treated and the condition of the patient.

In the combination therapies described herein, the doses of the co-administered compounds vary depending on the type of co-drug used, the specific drug

<img file="MX348290B_D0097.tif" />

The individual compounds of these combinations are administered either sequentially or simultaneously in individual or combined pharmaceutical formulations. In one embodiment, the individual compounds are administered simultaneously in a combined pharmaceutical formulation. Appropriate dosages of known therapeutic agents will be appreciated by those of skill in the art.

The combinations referred to herein are conveniently presented for use in the form of pharmaceutical compositions together with one or more pharmaceutically acceptable diluents or carriers.

In certain embodiments herein, a method for treating a cancer in an individual in need is disclosed, including: administering to the individual an amount of Compound 1. In some embodiments, the method further includes administering a second regimen. cancer treatment.

In some embodiments, the administration of a Btk inhibitor prior to a second cancer treatment regimen decreases immunologically mediated reactions to the second cancer treatment regimen. In some modalities, the administration of the

IMPPá

MEXICAN INSTITUTE

ICC DF LA FROHEt AL * CM ^{± uu} INDUSTRIAL

Compound 1 before ofatumumab decreases immunologically mediated reactions to ofatumumab.

In some embodiments, the second cancer treatment regimen includes a chemotherapeutic agent, a spheroid, an immunotherapeutic agent, a targeted therapy, or a combination of these. In some embodiments, the second cancer treatment regimen includes an inhibitor of the B cell receptor pathway. In some embodiments, the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCy inhibitor, an ΡΚΩβ inhibitor, or a combination of these. In some embodiments, the second cancer treatment regimen includes an antibody, a B-cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, a mTOR inhibitor, a radioimmunotherapeutic product, a DNA, a proteasome inhibitor, a Cyp3A4 inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, a Hsp90 inhibitor, a telomerase inhibitor, a Jakl / 2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination of these.

MEXICAN INSTITUTE.

_ M LA PROPIFTAf \ ^^ η2Η,? 5/167 INDUSTRIAL> t¿

In some modalities, the second cancer treatment regimen includes chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexametab, ibonaritum-101, CALIBONOMA-101 tositumomab, bortezomib, pentostatin, endostatin, or a combination of these.

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

In some modalities, the second cancer treatment regimen includes bendamustine, and rituximab.

In some modalities, the second cancer treatment regimen includes fludarabine, cyclophosphamide, and rituximab.

In some modalities, the second cancer treatment regimen includes cyclophosphamide, vincristine, and prednisone, and optionally rituximab.

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

In some modalities, the second regime of

ΙΜΡΙ ^ &lt;

INSTITUTO MEXICAN - zr, M LA FRoFieD *.

16 'industrial * cancer treatment includes dexamethasone and lenalidomide.

In some embodiments, the second cancer treatment includes a proteasome inhibitor. In some modalities, the second treatment includes bortezomib. In some modalities, the second cancer treatment includes an epoxyketone. In some modalities, the second cancer treatment includes epoxomycin. In some embodiments, the second cancer treatment includes a tetrapeptide epoxyketone. In some modalities, the second cancer treatment includes cariilzomib. In some modalities, the second cancer treatment includes disulfram, epigallocatechin-3-gallate, salinosporamide A, ONX 0912m CEP-18770, MLN9708, or MG132.

In some embodiments, the second cancer treatment includes a Cyp3A4 inhibitor. In some modalities, second cancer treatment includes indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone. In some modalities, the second cancer treatment includes ketoconazole.

In some modalities, the second cancer treatment includes a Janus Kinase (JAK) inhibitor. In some modalities, the second treatment includes Lestaurtinib, Tofacitinib, Ruxolitinib, CYT387, Baricitinib, or Pacritinib.

169 INSTITUTE MLXICAN

OF THE INDUSTRIAL Pt-jriEDAt

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

Other cancer treatment regimens include Nitrogen Mustards such as, for example, bendamustine, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, prednimustine, trophosphamide; Alkyl Sulphonates such as busulfan, mannosulfan, treosulfan; Ethylene Imines such as carboquone, thiotepa, triaziquone; Nitrosoureas such as carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, streptozocin; Epoxides such as, for example, ethoglucid; Other Alkylating Agents such as, for example, dacarbazine, mitobronitol, pipobroman, temozolomide; Folic Acid analogs such as, for example, methotrexate, permetrexed, pralatrexate, raltitrexed; Purine analogs such as, for example, cladribine,

170

IMPI ^ iNsrrruT · mlxican ·

M THE MOPIBILITY

<img file="MX348290B_D0098.tif" />

clofarabine, fludarabine, mercaptopurine, nelarabine, thioguanine; Pyrimidine analogs such as, for example, azacitidine, capecitabine, carmofur, cytarabine, decitabine, fluorouracil, gemcitabine, tegafur; Vinca alkaloids such as, for example, vinblastine, vincristine, vindesine, vinflunine, vinorelbine; Derivatives of Podophyllotoxins such as, for example, etoposide, teniposide; Colchicine derivatives such as, for example, demecholcin; Taxanes such as, for example, docetaxel, paclitaxel, paclitaxel polyglumex; Other Vegetable Alkaloids and Natural Products such as, for example, trabectedin; Actinomycin such as, for example, dactinomycin; Anthracyclines such as, for example, aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, zorubincin; Other Cytotoxic Antibiotics such as, for example, bleomycin, ixabepilone, mitomycin, plicamycin; Platinum compounds such as, for example, carboplatin, cisplatin, oxaliplatin, satraplatin; Methylhydrazines such as, for example, procarbazine; Sensitizers such as, for example, aminolevulinic acid, efaproxiral, methyl aminolevulinate, porfimer sodium, temoporfin; Protein Kinase Inhibitors such as, for example, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib,

<img file="MX348290B_D0099.tif" />

171

IMPI,

MEXICAN INSTITUTE

OF INDUSTRIAL MYSTERY pazonanib, sorafenib, sunitinib, temsirolimus; Other Agents

Antineoplastics such as, for example, alitretinoin, altretamine, amsacrine, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, denileucine 5 diftitox, estramustine, hydroxycarbamide, irinotecan, lonidagasone, masolimersine pentostatin, romidepsin, sitimagene ceradenovec, thiazofurin, topotecan, tretinoin, vorinostat; Estrogens such as, for example, diethylstilbenol, ethinyl estradiol, fosfestrol, polyestradiol phosphate; Progestins such as, for example, gestonorone, medroxyprogesterone, megestrol; Gonadotrophin Releasing Hormone Analogs such as, for example, buserelin, goserelin, leuprorelin, triptorelin; Anti15 Estrogens such as, for example, fulvestrant, tamoxifen, toremifene; Anti-Androgens such as, for example, Bicalutamide, Flutamide, Nilutamide, Enzyme Inhibitors, Aminoglutethimide, Anastrozole, Exemestane, Formestane, Letrozole, Vorozole; Other Hormone Antagonists such as, for example, abarelix, degarelix; Immunostimulants such as, for example, histamine dihydrochloride, mifamurtide, pidotimod, plerixafor, roquinimex, thymopentin;

Immunosuppressants such as, for example, everolimus, gusperimus, leflunomide, mycophenolic acid, sirolimus;

INSTITUTO MEXICANO -U DI LA ΓΒΟΡΙΡΠΑΟ C ΙΝΠΙΙΊΤΙΙΛΙ. "

Calcineurin inhibitors such as, for example, cyclosporine, tacrolimus; Other Immunosuppressants such as, for example, azathioprine, lenalidomide, methotrexate, thalidomide; and Radiopharmaceuticals such as, for example, iobenguan.

Other cancer treatment regimens include interferons, interleukins, Tumor Necrosis Factors, Growth Factors, or the like.

Other cancer treatment regimens include Immunostimulants such as, for example, ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, sargramostim; Interferons such as, for example, natural interferon alpha, interferon alpha-2a, interferon alpha2b, interferon alphacon-1, interferon alpha-nl, natural interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, peginterferon alfa-2a , peginterferon alfa-2b; Interleukins such as, for example, aldesleucine, or relvecin; Other Immunostimulants such as, for example, BCG vaccine, glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor, poly I: C, poly ICLC, roquinimex, tasonermine, thymopentin ; Immunosuppressants such as, for example, abatacept, abetimus, alefacept, antilymphocyte immunoglobulin (horse),

173 antithymocyte immunoglobulin

IMPI ₁NSTITUTO MEXICAN. PB LA FWoriBPAP INDUSTRIAL (rabbit)

<img file="MX348290B_D0100.tif" />

eculizumab, efalizumab, everoiimus, gusperimus, leflunomide, muromab-CD3, mycophenolic acid, natalizumab, sirolimus; TNF alpha inhibitors such as, for example, adalimumab, afelimomab, certolizumab pegol, etanercept, golimumab, infliximab; Interleukin inhibitors such as, for example, anakinra, basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept, tocilizumab, ustekinumab; Calcineurin inhibitors such as, for example, cyclosporine, tacrolimus; Other Immunosuppressants such as, for example, azathioprine, lenalidomide, methotrexate, thalidomide.

Additional cancer treatment regimens include Adalimumab, Alemtuzumab, Basiliximab, Bevacizumab, Certolizumab pegol, Daclizumab, Eculizumab, Efalizumab, Gemtuzumab, Ibritumomab tiuxetan, Infliximab, Muromonab-CD3, Natalibitumabitubitub, Panitumabituumab, Panitumabituumab, Panitumizumabituumab, Ranitumizumabituumab, etc. ., or a combination thereof.

Additional cancer treatment regimens include Monoclonal Antibodies such as, for example, alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gentuzumab, oifatumumab, panitumumab, rituximab, trastuzumab, Immunosuppressants, eizculizumab,

ΙΜΡΙ &amp;

MEXICAN INSTITUTE

4 I heard the industrial property muromab-CD3 ,, natalizumab; TNF alpha inhibitors such as, for example, adalimumab, afelimomab, certolizumab pegol, golimumab, infliximab, Interleukin inhibitors, basiliximab, canakinumab, mepolizumab, tocilizumab, ustekinumab, radiopharmaceuticals, ibtan, tosumab tiuxeumomab other Monoclonal Antibodies such as, for example, abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET MetMab monoclonal antibody, apolizumab, apomab, arcitumomab, basilixotimab, bi-specific antibody to capromab1, pennatuxima bi-specific antibody 2B1, biospecific blomatabomabomaboma 2B1 biospecific antibody , cixutumumab, claudiximab, conatumumab, dacetuzumab, denosumab, eculizumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab, ganitumab, gemtuzumab oxogamicin, glembatumumab, ibritumomab, inotuzumab ozogamicin, ipilimumab, Lexatumumab, lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, necitumumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab, ramacurimab, ranibizumab, siplizumab, sonepcizumab, tanezumab, tositumomab, trastuzumab, tremelimumab , tucotuzumab celmoleucine, veltuzumab, visilizumab, volociximab, zalutumumab.

Additional regimens for cancer treatment include agents that affect the tumor microenvironment such as the cellular signal network (for example, the phosphatidylinositol 3-kinase (PI3K) signal from the industrial currency, signals from the B cell receptor and IgE receptor.) 'In some forms, the second agent is the PI3K signal inhibitor or a syc kinase inhibitor. In one form, the syk inhibitor is R788. In another form, it is a PKCy inhibitor such as for example enzastaurin.

Examples affecting the tumor microenvironment include PI3K signal inhibitor, syc kinase inhibitor, Protein Kinase Inhibitors such as, for example, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, sorafenib, sunitinib, temsirolimus ; other Angiogenesis Inhibitors such as, for example, GT-111, JI-101, R1530; other Kinase Inhibitors such as, for example, AC220, AC480, ACE-041, AMG 900, AP24534, Arry-614, AT7519, AV-951, axitinib, AZD1152, AZD7762, AZD8055, AZD8931, bafetinib, BAY 73-4506, BGJ226, BGT226, BI 811283, BI6727, BIBF1120, BIBW 2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036, dinacyclib, E70inib lactate , EMD 1214063, ENMD-2076, fostamatinib disodium, GSK22566098, GSK690963, INCB18424, INNO-406, JNJ-26483327, JX-594, KX2391, linifanib, LY2603618, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON 01919.Na, OSI027, OSI-930, Btk inhibitor, PF-005562271, PF-0217341066

<img file="MX348290B_D0101.tif" />

03814735, PF-04217903, PF04554878, PF-046915727'PF 3750309_r

PHA-73958, PLC3397, progenipoietin, R574, R763, ramucirumab, regorafenib, RO5185426, SAR103168, SCH 727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TL607, XL14TP, TL607-232, TKI258, TL607, XL14TP , XL228, XL281RO5126766, XL418, XL765.

Additional examples of anticancer agent for use in combination with a Btk inhibitor compound include mitogen activated protein kinase signal inhibitors, eg, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (eg, rituxan).

Other anticancer agents that can be employed in combination with a Btk inhibitor compound include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronin;

adozelesin; aldesleucin; altretamine; ambomycin; methantrone acetate; aminoglutethimide; amsacrine; anastrozole: antramycin; asparaginase; asperlin; azacitidine; azotomycin; batimastat; benzodepa; bicalutamide; bisanthrene hydrochloride; bisnafide dimesitylate; bizelezin; bleomycin sulfate; brequinar sodium; bropyrimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; Carubicin Hydrochloride;

<img file="MX348290B_D0102.tif" />

carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine;

chrysnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; Caunorubicin Hydrochloride; decitabine; dexormaplatin; dezaguanine; Dezaguanine Mesylate; diaziquone; doxorubicin; Doxorubicin Hydrochloride; droloxifene; Droloxifene Citrate; dromostanolone propionate; duazomycin; edatrexate; Eflornithine Hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; Epirubicin Hydrochloride; erbulozola; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposido; etoposide phosphate;

ethoprine; Fadrozole Hydrochloride; fazarabine; fenretinide;

floxuridine; Fludarabine Phosphate; fluorouracil;

flurocitabine; phoschidone; fostriecin sodium; gemcitabine; Gemcitabine Hydrochloride; hydroxyurea; Idarubicin Hydrochloride; ifosfamide; iimophosine; interleukin II (including recombinant interleukin II or rII2), interferon alfa-2a; interferon alfa-2b; interferon alpha-nl; interferon alpha-n3; interferon beta-la; interferon gamma-1 b; iproplatin; Irinotecan Hydrochloride; Lanreotide Acetate; letrozole; Leuprolide Acetate; liarozola hydrochloride; lometrexol sodium; lomustine; Losoxantrone Hydrochloride; masoprocol; maytasine; Mechlororetamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate;

melphalan;

menogaril;

IMPI (HST1TUTO MLXlCAN · Di LA HUMEDAD INDUSTRIAL mercaptopurinda;

methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogilin; mitomalcin; mitomycin; mitosper; mitotane; Mitoxantrone Hydrochloride; mycophenolic acid; mocodazoia; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; Peplomycin Sulfate; perfosphamide; pipobroman; piposulfan; Pyroxantrone Hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; Procarbazine Hydrochloride; puromycin; Puromycin Hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; sytrazene; sodium sparphosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; Teloxantrone Hydrochloride; temoporfin; teniposide; teroxyrone; testolactone; thiamiprine; thioguanine; thiotepa; thiazofurin; tirapazamine; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; trimetrexate; glucuronate trimetrexate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; Vinblastine Sulfate; Vincristine Sulfate; vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; sulfate

179 ΙΜΡΓ ^

Κ &lt;ΤΓΠΠ &lt;- MEXICAN vinrosidine; Vinzolidine Sulfate; vorozola,^piθκτιίρΐ ¿ιΤ? 4? Γ zinostatin; zorubicin hydrochloride. - *

Other anticancer agents that can be used in combination with a Btk inhibitor compound include: 20-epi1, 25-dihydroxy vitamin D3; 5-ethynyluracil; abiraterone;

aclarubicin; acylfulvene; adecylpenol; adozelesin; adldesleucin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; amino levulinic acid; amrubicin; amsacrine; anagrelide; anastrozola; andrographolide;

angiogenesis inhibitors; antagonist Antagonist D;

antagonist G; antarelix; morphogenetic anti-dorsalizing protein-1; antiandrogen, prosthetic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azathyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorines; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantreno; bisaziridinyl spermine; bisnafide; bistratene A; bizelesin; breflate; bropyrimine; budotitan;

butionine sulfoximine; calcipotriol; calfostin C; derivatives

<img file="MX348290B_D0103.tif" />

IMPI INSTITUTO MLXICAN. _or „Ce la mohedal

INDUSTRIAL OU of camptotecin; canarypox IL-2; Capecitabine; carboxamideamino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrolix; chlorines; chloroquinoxaline sulfonamide; cacaprost; cis-porphyrin; cladribine; Clomiphene Analogs;

clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analog; conagenin; crambescidin 816; cristanol; cryptophycin 8; derivatives of cristoficin A; cure A; cyclopentanthraquinones; cycloplatam; cpemicycin; Cypemycin; Cytarabine Ophosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexyphosphamide; dexrazoxane; desverapamil; diaziquone; didemnin B; didoex; diethylnospermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxyfluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelphosine; edrecoiomab; eflornithine; elemene; emitfur; epirubicin; epristerido; estramustine analog; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozola; fazarabine; fenretinide; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium

181 texapirin;

gallium nitrate inhibitors; galocytabine; ganirelix;

gelatinase; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; Hexamethylene Bisacetamide;

hypericin; Ibandronic acid; idarubicin; idoxifene;

idramantone; ilmophosine; ilomastat; imidazoacridones;

imiquimod; immunostimulating peptides; insulin such as for example growth factor-1 receptor inhibitor; interferon agonists; interleukins; iobenguan; iododoxorubicin; ipomeanol, 4; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolido; Jasplakinolido; kahalalide; lamelarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; interferon alpha leukocyte; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozola; linear polyamine analog; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; earthworm; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetio texafrin; lysophylline; Uotic peptides; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarona; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; Ragged double stranded RNA;

₁₈₂ IMPIAS

-¹ ° fNSTmJTU MEJtICAN

DE LA Pt <> HEDAf V * · * mitoguazone; mitolactol; mitomycin analogs; mitonatidaT saporin fibroblast growth factor mitotoxin; ' mitoxantrone; Mofarotene; molgramostim; monoclonal antibody; human chorionic gonadotropin; monophosphoryl lipid A + sk from the myobacterial cell wall; multiple drug resistance gene inhibitor; therapy based on multiple tumor suppressor 1; Mustard anticancer agent; mycaperoxide B; Mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavin; nafterpin; nartograstim; nedaplatin; nemorubicin; Neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrulin; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondasetron; prayer; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamina; palmitoyl rhizoxin; Pamidronic acid; panaxytriol; panomiphene; parabactin; pazeliptin; pegaspargasa; peldesine; pentosan polysulfate sodium; pentostatin; pentrozola; perflubron; perfosphamide; perilic alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; Pilocarpine Hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex;

<img file="MX348290B_D0104.tif" />

IMPI «mnOMUICAN • t LA Hohf n»! .

platinum compounds; platinum-triamine complex; porfimeT · sodium; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; Protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; glitter; pyrazoloacridine; pyridoxylated polyoxyethylene hemoglobin conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated reteliptin; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukina; roquinimex; rubiginone Bl; ruboxil; salfingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparphosic acid; spicamycin D; spiromustine; splenoepentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; vasoactive intestinal peptide antagonist

<img file="MX348290B_D0105.tif" />

184 overactive; suradista;

synthetic glycosaminoglycans;

suramin;

talimustine;

IMPT • ^ dustrul swainsonine tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrillium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodeca oxide; tetrazomine; taliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; timalfasin; thymopoietin receptor agonist; timotrinan; thyroid stimulating hormone; tin ethyl ethiopurpurin; tirapazamine; titanocene dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triporelin; tropisetron; turosteride; tyrosine kinase inhibitors; thyphostines; UCB inhibitors; ubenimex; growth inhibitory factor derived from urogenital sinus; urokinase receptor antagonists; vapreotid; variolin B; vector system, erythrocyte gene therapy; velaresol; veramin; verdinas; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozola; zanoterone; zeniplatin; zilascorb; and zinostatin estimalamer.

Still other anticancer agents that can be employed in combination with a Btk inhibitor compound include alkylating agents, antimetabolites, natural products, or hormones, for example nitrogen mustards (for example, mechloroethamine, cyclophosphamide, chlorambucil, etc.),

<img file="MX348290B_D0106.tif" />

185

IMPI;

'wrnn-OMmcAN Dt LA Mi KIEüAi'NOUSTRIAl alkyl sulphonates (eg carmustine, eg busulfan), nitrqsoureas (for lomustine, etc.) or triazenes (decarbazine, etc.). 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 employed in combination with a Btk inhibitor compound include but are not limited to nitrogen mustards (eg, mechloroethamine, cyclophosphamide, chlorambucil, meifalan, etc.), ethyleneimine, and methylmetalines (eg, hexamethyl melanin, thiotepa), alkyl sulfonates (eg busulfan), nitrosoureas (eg carmustine, lomustine, semustine, streptozocin, etc.) or triazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analogs (eg, methotrexate) or pyrimidine analogs (eg, fluorouracil, floxouridine, Cytarabine), purine analogs (eg, mercaptopurine, thioguanine, pentostatin). .

Examples of anticancer agents that act by retaining cells in the G2-M phases due to stabilized microtubules and that can be used in combination with a Btk inhibitor compound, include without limitation

186

<img file="MX348290B_D0107.tif" />

following drugs marketed and medicate me '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 (Abbott, also known as E7010), Altorhyrtins (such as Altorhyrtin A and Altohyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9), Cemadotin hydrochloride (also known as LU103793 and NSC-D-669356), Epothilones (such as Epothilone A and Epothilone B ), Epothilone C (also known as desoxiepotilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxiepothilone B), Epothilone E, 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 Desoxiepothilone F and dEpoF), 26-fluorine epothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT -1027), LS-4559-P (Pharmacia, also known as LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daii chi), FR-182877 (Fujisawa, also known as

IMPIg τ or τ ΠΓΠΤυΤΟ MU ICA NO lo / DE LA CURN I ^ L ·

INDUSTRIAL> 5

WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Cruptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39 HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39L-Ser.HCI and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),

T-138067 (Tularik, also known as T-67, TL-138067 and TI-13867), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin Al (also known as BTO-956 and DIME), DDE-313 (Parker Hughes In stitute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKETP), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T138026 (Tularik), Monsatrol, Inanocine (also known as

<img file="MX348290B_D0108.tif" />

188

ΙΜΡΪ ^ mexican institute

OF THE PIIOMH'A »INDUSTRIAL

NSC-6987666), 3-IAABE (Cytoskeleton / Mt. Sinai School of

Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethylleutherobin, Desacetyl eleutherobin, Isoeleutherobin A and Z-Eleutherobin), Caribaeosido, Caribaeolin, Halichondrin b, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A- 259754 (Abbott), Diozostatin, (-) Phenilahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, tri-fluorine acetate salt) Wyeth), D-82317 (Zentaris) ,, D-82318 (Zentaris) ,, SC-12983 (NCI), Resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes) and SSR- 250411 (Sanofi).

When the person is suffering from or is at risk of an autoimmune disease, an inflammatory disease, or an allergic disease, Compound 1 can be used with one or more of the following therapeutic agents in any combination: immunosuppressants (eg, tacrolimus, cyclosporin, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (eg, prednisone, acetate

<img file="MX348290B_D0109.tif" />

189

IMPI

INSTITUTO MEXICANO DE LA FMFIEBAD INDUSTRIAL of cortisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone, beclomethasone acetate, deoxycorticosterone acetate, aldosterone (for example non-spheroidal spheroidal acids, - noic, 2-arylpropionic acids, Narilanthranilic acids, oxicams, coxibs or sulfonanilides), Cox-2 specific inhibitors (for example, valdecoxib, celecoxib or rofecoxib), leflunomide, thioglucose gold, thiomalate gold, aurofin, sulfasalazine, hydroxychlor quinine, minocycline, TNF-alpha binding proteins (eg, ínfliximab, etanercept, or adalimumab) abatacept, anakinra, interferon-beta gamma, interleukin-2, allergy shots, antihistamines, antileukotrienes, beta agonists, theophylline, or anticholinergics.

Cases / Articles of Manufacture

For use in the therapeutic methods of use described herein, kits and articles of manufacture are also described. Such kits include a vehicle, package, or container that is compartmentalized to receive one or more packages such as bottles, tubes, etc., each of which comprises one of the separate elements to be used in a method described herein. Appropriate containers include, for example, bottles, vials, syringes, and tubes of

190 proof. In one form, the containers are materials such as glass and plastic.

JMPJ 'NOUSTRml

<img file="MX348290B_D0110.tif" />

s of several

The articles of manufacture provided here contain packaging materials. Packaging materials for packaging pharmaceutical materials include but are not limited to blister packages, bottles, tubes, bags, containers, and any appropriate packaging materials for a selected preparation and proposed mode of administration and treatment.

In some forms, the compounds or compositions described herein are presented in a package or dispensing device that may contain one or more unit dosage forms containing the active ingredient. The compound or composition described herein is packaged alone or with another compound or other ingredient or additive. In some forms, the package contains one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. In some forms, the package comprises foil or plastic, such as a blister-type package. In some forms, the package or dispensing device is accompanied by instructions for administration, such as instructions for administering the compounds or compositions intended for the treatment of neoplastic disease. In some forms, the packaging or dispenser is accompanied by an associated notice

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Q1 M LA MOHEDA. Cw ^ —JT ± ^ ± INDUSTRIAL with the container in the manner prescribed by the governmental regulatory agency for the manufacture, use or sale of pharmaceutical products; such notice reflects the agency's approval of the drug form for human or veterinary administration. In some forms, such notice is, for example, the US Food and Drug Administration approved label for prescription drugs or the approved literature for the product. In some forms, compositions that include a compound as described herein are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

For example, the package (s) include Compound 1, optionally in a composition or in combination with another agent as described herein. Such kits optionally include an identifying description or label or instructions regarding their use in the methods described herein.

A kit typically includes labels with lists of contents and / or instructions for use and literature with instructions for use. An instruction set will also typically be included.

In one form, a label is associated with the container. In one form, a label is found on the container when the letters, numbers, or other characters that make up

<img file="MX348290B_D0111.tif" />

192

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M THE INDUSTRIAL PROPERTY to the label are attached molded or etched on the container itself; A label is associated with a container when it is within a receptacle or carrier that contains the container, for example, such as literature for packaging. In one form, a label is used to indicate that the content is to be used for a specific therapeutic application. The label also contains the instructions for use of the content, such as in the methods described here.

In certain forms, the pharmaceutical compositions are presented in a package or dispenser device containing one or more unit dosage forms that carry a compound provided herein. For example, the package contains foil or plastic, such as a blister-type package. In one form, the package or dispensing device is accompanied by instructions for administration. In one form, the packaging or dispenser is also accompanied by a notice associated with the container, in the form prescribed by the governmental agency that regulates the manufacture, use or sale of pharmaceutical products and which reflects the approval of the form of the drug. for human or veterinary administration. For example, such a notice is the label approved by the US Food and Drug Administration for prescription drugs or the approved literature for the product. In

193 NDUSTRIaI if some forms, compositions including a compound as described herein, are prepared, placed in an appropriate container and labeled for treatment of an indicated condition.

EXAMPLES

The following ingredients, preparations, processes and procedures for practicing the methods described herein correspond to those described above.

Example 1: Preparation of the Crystalline Forms of 1- ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-l-yl) piperidin-l -il) prop-2-en-l-one (Compound 1)

Form A - Route 1:

Amorphous Compound (approximately 15 mg) was measured in a bottle. Ten volumes (150 μΐ) of solvent [methyl tertiary butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, propyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, methanol, nitromethane, 10% aqueous acetone, or 10% aqueous isopropyl alcohol). The bottle was sealed and placed on a shaker at 50 ° C for one hour. If a paste formed, an additional thirty volumes (600 µΐ total) of solvent was added and then the paste was placed back at 50 ° C for another hour. If the sample remained as a paste at this point,

IMPI

INSTITUTO MEXICANO Di LA PROPIEDAD INDUSTRIAL no additional solvent was added. The solution / paste was stirred at 50 ° C for one hour then cooled to 0 ° C at 0.1 ° C per minute and kept at 0 ° C overnight. If a paste forms, the solids are filtered under vacuum to provide Compound 1, Form A .; The solution was returned to room temperature for slow evaporation through a tiny hole to supply Compound 1, Form A.

Form A - Route 2

Amorphous Compound 1 (20 mg) was added to a bottle, followed by solvent [heptanes (10 volumes), dioxane (1 volume), toluene (10 volumes), MTBE (10 volumes), DIPE (10 volumes), anisole ( 1 volume), ethyl acetate (10 volumes), isopropyl acetate (10 volumes), tetrahydrofuran (1 volume), DCM (1 volume), MIBK (10 volumes), MEK (10 volumes), acetone (10 volumes), methanol ( 10 volumes), ethanol (10 volumes), acetonitrile (10 volumes), nitromethane (1 volume), water (10 volumes) or 10% aqueous isopropyl alcohol (1 volume)]. The sealed bottle was placed in a ripening chamber (cycles between 50 ° C and room temperature for four hours each) for five days before filtering the solids under vacuum to provide Compound 1, Form A.

In some forms, amorphous Compound 1 is prepared

IMPIí ^

195 MEXICAN INSTITUTE

I heard LA FU 'IPIEDAD CV-W INDUSTRIAL dissolving Compound 1, Form A (approximately 500 mg) in 10 ml of dichloromethane (DCM). The solvent is removed by rotary evaporation, quite quickly to avoid crystallization and to obtain amorphous Compound 1.

Form A - Route 3:

[00368] In a clean round bottom flask, 12.0 grams of Compound 1 was dissolved in 120 ml of methanol by heating to 45 ° C with magnetic stirring. To the hot solution of dissolved Compound 1, 72 ml of water was added over 45 minutes, keeping the internal temperature at 45 ° C. The solution was slowly turned into a paste and stirred for 3 hours at elevated temperature. The paste was sampled and filtered and dried. The paste was allowed to cool to room temperature and stirred for at least 16 hours. Another sample of the pulp was taken and filtered and dried. The solids were filtered, washed with 50 ml of a 3: 2 methanol: water mixture and dried on the filter for 40 hours. 9.6 grams of Form A were produced (melting points: first sample approx. 152 ° C, second sample approx. 154 ° C, main batch approx. 154 ° C).

Form A was made in a similar way using aqueous acetone, ethanol, and n-propanol.

Form B - Route 1:

Compound 1, Form A (approximately 100 mg) was weighed

<img file="MX348290B_D0112.tif" />

into a container and dissolved in methanol (2 ml). The solution was heated to 50 ° C to ensure complete dissolution and then cooled to 5 ° C. Water was added to the solution at 5 ° C (200 µΐ in one go until the sample turned cloudy, for a total of 1000 µΐ). Seed of Compound 1, FormaC, was added immediately after the appearance of turbidity. The paste was stirred at 5 ° C for one day. An aliquot was pipetted for analysis by X-ray Powder Diffraction (XRPD), keeping the sample volume under the same conditions. XRPD analysis highlighted the low crystallinity of the material, so that the sample was kept at 5 ° C for an additional three days. After this time, a new analysis of an aliquot of the sample showed that the material converted to Compound 1, Form B. The sample was separated by vacuum filtration to provide Compound 1, Form B.

Form B - Route 2:

Compound 1, Form A (approximately 500 mg) was weighed into a container and dissolved in methanol (4 ml) at 50 ° C. The solution was cooled to 25 ° C, remaining in solution. Water (500 µΐ of water in one go, 2 ml in total) was added until the solution turned cloudy. The paste was stirred for ten minutes. An aliquot was pipetted to assess the material by XRPD shaking the sample at 25 ° C for one hour; s the material had a very low crystallinity. After one hour of stirring at 25 ° C, the sample was placed at 5 ° C for three days. After that time, another aliquot was pipetted for XRPD analysis. The rest of the paste was filtered under vacuum and dried at 25 ° C. Vacuum overnight to provide Compound 1, Form B.

Form C:

In a clean round bottom flask, 2.0 grams of Compound 1 was suspended in 25 ml of methanol and heated to 50 ° C. The hot solution of dissolved Compound 1 was filtered into a clean round bottom flask. The clean solution was allowed to cool to room temperature with magnetic stirring. The solution slowly turned into a paste and was stirred for 14 hours. The solids were filtered, washed with 5 mL of methanol and dried on the filter for 20 hours and then at 50 ° C in a vacuum oven for 8 hours. 1.4 grams of Form C were produced (melting point = approx. 132 ° C) '.

Form D:

A dry mix (approximately 5 mg of each component) was prepared using two of Form A, Form B or Form C of Compound 1. A paste prepared with the

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INSTITUTO MfcXICAN Di LA MONEDAD industrial

Compound 1 amorphous in MIBK to obtain a saturated solution. Ten volumes (100 µΐ) of the saturated solution were added to the dry mix to prepare a new paste. The pulp was stored at 5 ° C for three days before vacuum filtration to provide Compound 1, Form D.

Form E:

Amorphous Compound 1 (20 mg) was added to a bottle, followed by Compound 1, Form C seeds (approximately 5 mg). Ten volumes of toluene (200 µΐ) were added to the bottle to make a paste. The bottle was sealed and allowed to mature (cycles between 50 ° C and room temperature for four hours each) for one day. An aliquot was pipetted for analysis by XRPD, TGA, and DSC; the data were consistent with Compound 1, Form E. However, this compound was found to have converted to Compound 1, Form A after standing at room temperature overnight at 40 ° C under vacuum for one day.

Form F:

In each clean 20 ml scintillation flask, 200 mgs of Compound 1 and 50 mgs of activated charcoal were suspended in 4 ml of methanol and heated to 50 ° C. The resulting mixture was stirred at 50 ° C for 2.5 hours. The

199 JMPI

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<img file="MX348290B_D0113.tif" />

through a syringe filter into a new clean bottle Uí?

mi, removing charcoal. The clean solution was allowed to cool to room temperature. Without stirring, the solution was aged for one week when the formation of some crystals was observed. After a further 6 weeks, the bottom of the bottle was covered with large crystals. The crystals were kept under methane solution! supersaturated for analysis.

Example 2: X-ray Powder Diffraction (SRPD)

X-ray powder diffraction patterns were collected on a Bruker AXS C2 GADDS or Bruker AXS D8 diffractometer.

Bruker AXS C2 GADDS

X-ray Powder Diffraction patterns were collected on a Bruker AXS 02 GADDS diffractometer using Cu Ka radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for sample self-placement, and area detector. HiStar two-dimensional. The X-ray optical system consists of a single Góbel multilayer mirror coupled with a 0.3 mm tiny hole collimator. A weekly performance check was performed using a certified standard NIST 19976 Corundum (flat plate). The beam divergence, that is, the effective size of the X-ray beam on the sample was approximately 4 mm. I know

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INSTITUTO MF.XICAN «ΙΛΜ.ΦΙΕΡΑΓ Λ used the continuous scanning mode Θ-Θ with a 20 cm dS'éffSWciy sample-detector, which gives a scale of 'éiéULiVd 20 ·¹3.2 ° -29.7 °. Typically, the sample could be exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for WNT 4.1.16 and the data were analyzed and presented using Diffrac Plus EVA vll-0.0.2 or vl3.0.0.2.

Ambient Conditions

Samples passed under ambient conditions were prepared as flat plate specimens using the powder as received without grinding. About 1-2 mg of the sample was lightly pressed onto a glass stage to obtain a flat surface.} Non-Ambient Conditions

Samples passed under non-ambient conditions were mounted on a silicone wafer with a heat conducting compound. The sample was then heated to the appropriate temperature at 10 ° C / minute (unless otherwise noted) and was subsequently held isothermal for 1 minute before starting data collection.

Bruker AX D8 Advance

Dust Diffraction patterns were collected by Rayox X on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA), Θ-2Θ goniometer and V4 divergence, with slots

<img file="MX348290B_D0114.tif" />

receivers, a Ge monochromator and a Lynxeye detector. Instrument performance is verified using a certified Corundum standard (NIST 19976). The software used for data collection was Difrrac Plus XRD Commander v2.5.0 and the data was analyzed and presented using Diffrac Plus EVA vil.0.02 or V13.0.0.2. The samples were run under ambient conditions as flat plate specimens using the powder as received. The sample was gently placed in a cavity made in the polished silicon wafer with a zero black background (510). The sample was rotated in its own plane during analysis. The details of the data collection are:

Angular scale: 2 to 42 ° 29

Step size: 0.05 ° 2θ

Collection time: 0.5 s / step

XRPD in Form A

X-ray powder diffraction for Form A is illustrated in Fig. 1. Characteristic ridges include 5.7 + 0.1 ° 2-Theta, 13.6 + 0.1 ° 2-Theta, 16, 1 + 0.1 ° 2-Theta, 18.9 + 0.1 ° 2-Theta, 21,310.1 ° 2-Theta and 21,610.1 ° 2-Theta.

The crystallinity was not affected after one week of storage at 40 ° C / 75% relative humidity or after one week of storage at 25 ° C / 97% relative humidity.

202 ΙΜΡΓίϋ

XRPD in Form B \

X-ray diffraction for Form B is illustrated in Fig. 5. Characteristic ridges include 5,210.1 ° 2-Theta, 10,210.1 ° 2-Theta, 16,510.1 ° 2-Theta, 18.5+ 0.1 ° 2-Theta and 20.8 ± 0.1 ° 2-Theta.

The crystallinity was not affected after one week of storage at 40 ° C / 75% relative humidity or after one week of storage at 25 ° C / 97% relative humidity.

XRPD in Form C

X-ray powder diffraction for Form C is illustrated in Fig. 9. Characteristic ridges include 7.0 + 0.1 ° 2-Theta, 14.0 + 0.1 ° 2-Theta, 15, 7 + 0.1 ° 2-Theta, 18,210.1 ° 2-Theta, 19,110.1 ° 2-Theta, 19.5 + 0.1 ° 2-Theta, 20,310.1 ° 2-Theta, 22,110.1 ° 2-Theta and 22.9 + 0.1 ° 2-Theta.

The crystallinity was not affected after one week of storage at 40 ° C / 75% relative humidity or after one week of storage at 25 ° C / 97% relative humidity.

XRPD in Form

X-ray powder diffraction for Form D is illustrated in Fig. 12. Characteristic ridges include 7,210.1 ° 2-Theta, 8,010.1 ° 2-Theta, 9,210.1 ° 2-Theta, 14, 5 + 0.1 ° 2-Theta, 18.5 + 0.1 ° 2-Theta, 19.5 + 0.1 ° 2-Theta,

<img file="MX348290B_D0115.tif" />

21.0 ± 0.1 ° 2-Theta

21,9±0,1°

203

2-Theta

22,4±0,1°

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XRPD in Form E

X-ray powder diffraction for Form E is illustrated in Fig. 14. Characteristic ridges include 7.8 ± 0.1 ° 2-Theta, 8.8 ± 0.1 ° 2-Theta, 16, l ± 0, l ° 2-Theta, 18, l ± 0, l ° 2-Theta, 19.3 + 0.1 ° 2-Theta, 19.5 ± 0, l ° 2-Theta, 20.5+ 0.1 ° 2-Theta, 21.6 ± 0, l ° 2-Theta and 25.2 ± 0, l ° 2-Theta.

XRPD in Form F

A simulated XRPD pattern was generated for Form F. This XRPD simulator pattern was generated from the single crystal data obtained in Example 3 (see file) using Mercury CSD v3.1 (CF Macrae et al., J. Appl. Cryst. (2006), 39-3, 453-457 (XRPD pattern settings: Cuka 1.54056; Start / End 2/43 20 °; PWHW (2nd) 0.1). The data was then saved as a raw file To generate the 20 ° peak / Intensity (%) table, the raw file was processed using Diffrac Plus EVA v. 15.0.0.0.

The simulated X-ray powder diffraction pattern for Form F is illustrated in Fig. 16. Characteristic ridges include 6.2 ± 0.1 ° 2-Theta, 10.1 ± 0.1 ° 2-Theta,

17.6 ± 0, l ° 2-Theta, 18.6 ± 0, l ° 2-Theta, 20.0 ± 0, l ° 2-Theta,

20.4 ± 0, l ° 2-Theta, 20.7 ± 0, l ° 2-Theta, 22.4 ± 0, l ° 2-Theta,

23.0 ± 0, l ° 2-Theta, 23.2 ± 0, l ° 2-Theta, 24.4 ± 0, l ° 2-Theta,

25, l ± 0, l ° 2-Theta, 27.6 + 0.1 ° 2-Theta, 29.3 ± 0, l ° 2-Theta and

<img file="MX348290B_D0116.tif" />

204

29.7 + 0.1 ° 2-Theta.

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Example 3: X-ray diffraction of a single crystal. Single crystal X-ray diffraction data was collected and processed as follows:

<td>Diffractometer</td><td>SuperNova, Dual, Cu to Zero, Atlas</td>

<td>Radiation Source</td><td>X-ray source SuperNova (Cu), CuKa</td>

<td>Gathering Method Data</td><td>Omega scans</td>

<td>Theta scale for data collection</td><td>9.11 to 74.49 °</td>

<td>Index scales</td><td>-11 &lt;h &lt;12, -12 &lt;k &lt; 12, -18 &lt;1 &lt;18</td>

<td>Reflections collected</td><td> 22842</td>

<td>Independent reflections</td><td>9278 [R (int) = 0.0407]</td>

<td>Coverage of independent reflections</td><td> 99, 4%</td>

<td>Variation in check reflections</td><td>Not applicable</td>

<td>Absorption correction</td><td>Semi-empirical from equivalents</td>

<td>Maximum and minimum transmission</td><td>1.00000 and .73583</td>

<td>Solution technique structure</td><td>Direct</td>

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<td>Structure solution program</td><td>SHELXS-97 (Sheldrick, 1990)</td>

<td>Refining technique</td><td>Least squares to full matrix in F²</td>

<td>Refining program</td><td>SHELXS-97 (Sheldrick, 1997)</td>

<td>Minimized function</td><td>Σω (F_OR²-F_C²)²</td>

<td>Data / Restrictions / Parameters</td><td> 9278/3/660</td>

<td>or Goodness of adaptation in F</td><td> 1.004</td>

<td>Δ / o_max</td><td> 0,000</td>

<td>Final R indices 9185 data; Ι&gt; 2σ (Ι) All data</td><td>R1 = 0.0414, wR2 = 0.1144 Rl = 0.0417, wR2 = 0.1149</td>

<td>Weighing scheme</td><td>Cale w = 1 / [o²(F₀²) + (0.0810P)²+ 0.2800P] in which P = (FO² + 2FC²)/3</td>

<td>Structure parameter absolute</td><td> -0,01(13)</td>

<td>Extinction coefficient</td><td> 0,0013 (3)</td>

<td>Larger ridge and differential hole.</td><td>0.320 and -0.285 eÁ '^J</td>

206

The

Form F is

IMPIAS,. ,,, IMSTTTUTl) MEXICAN ^ characterized by parameters^DS^ »^ Unit approximately equal to the following at a temperature of approximately 100 (2) K:

<td>Mole Formula- cular</td><td colspan="5">C53H60N12O7</td>

<td>Weight Molecular</td><td colspan="5"> 977,13</td>

<td>System of crystal</td><td colspan="5">Triclinic</td>

<td rowspan="3">Group of space</td><td rowspan="3">PI</td><td>to</td><td>9, 6332 (3) A</td><td>to</td><td> 105,762(3)⁰</td>

<td>b</td><td>9.7536 (4) Á</td><td>β</td><td> 95,132(2)⁰</td>

<td>c</td><td>15.0592 (4) Á</td><td>AND</td><td> 111,332 (3)°</td>

<td>V</td><td colspan="5">1240.15 (7) Á³</td>

<td>Density (calculated)</td><td colspan="5">1.308 Mg / m³</td>

<td>Coefficient absorption</td><td colspan="5">0.72 6 mm '¹</td>

<td>Lenght of wave</td><td colspan="5">1.54178A</td>

<td>F (000)</td><td colspan="5"> 518</td>

<td>T</td><td colspan="5">100 (2) K</td>

Example 4: Fourier transformation - Infrared (FTIR)

Data was collected on a Perkin-Elmer Spectrum One apparatus fitted with an Attenuated Total Reflectance (ATR) sampling accessory. Data was collected and analyzed using Spectrum v5.0.1 software.

<img file="MX348290B_D0117.tif" />

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Fig. 2 illustrates the infrared spectrum for Form A. Characteristic peaks observed in the infrared spectrum for Form A include peaks at: 1584 cm '¹'' 1240 cm^-1, 1147 cm^-1, 1134 cm '¹, 1099 cm '¹, 1067 cm '¹ and 953 cm '¹.

The infrared spectrum for Form B is shown in Fig. 6. Characteristic peaks observed in the infrared spectrum for Form B include peaks at: 1586 cm '¹, 1573 cm '¹, 1562 cm '¹, 1229 cm '¹, 1166 cm '¹, 1141 cm '¹, 1103 cm '¹, 1056 cm '¹, 1033 cm '¹ and 982 cm '¹.

Example 5: Differential Scanning Calorimetry (DSC) and Thermo-Gravimetric Analysis

DSC data was collected on a TA Instruments Q2000 equipped with a 50 position autosampler. Thermal capacity calibration was performed using sapphire and energy and temperature calibration was performed using certified Indium. Typically 0.5-3 mg of each sample was heated, in an aluminum container fitted with tiny holes, at 10 ° C / minute from 25 ° C to 300 ° C. A dry nitrogen purge was maintained on the sample at 50 ml / minute, unless otherwise indicated. Differential Scanning Calorimetry was performed at modulated temperature using an underlying heating regime of 2 ° C / minute and temperature modulation parameters of ± 0.318 ° C (amplitude) every 60 seconds (period. The instrument control software was Advantag for Series Q v2.8.0.392 and Thermal Advantage v4.8.3 and the data was analyzed using Universal Analysis v4.4^to.

Thermogravimetric Analysis data was collected on TA Instruments Q500 TGA, equipped with a 16-position autosampler. The instrument temperature was calibrated using certified Alumel and Nickel. Typically, 3-10 mg of each sample was loaded into a pre-graduated aluminum DSC container heated at 10 ° C / minute from room temperature to 350 ° C. A nitrogen purge was maintained on the sample at 60 ml / minute, unless otherwise indicated. The instrument control software was Advantage for Q Series v2.8.0.392 and Thermal Advantage v4.8.3 and the data was analyzed using Universal Analysis v4.4A.

Form a

Fig. 3 and Fig. 4 present the DSC and TGA thermograms for Form A respectively.

No weight loss was observed. The material is anhydrous.

In DSC (heating rate: 10 ° C / minute or 20 ° C / minute) an endotherm was observed with a beginning at plus or minus 154 ° C and a peak at plus or minus 157 ° C. An exothermic peak was observed at 159 ° C.

Form b

Fig. 7 and Fig. 8 present the DSC and TGA thermograms for Form B respectively.

No weight loss was observed. The material is anhydrous.

In DSC (heating rate: 10 ° C / minute or 20 ° C / minute) an endotherm was observed with a start at plus or minus 99-106 ° C and a peak at plus or minus 115-118 ° C.

Form C

Fig. 10 and Fig. I show the DSC and TGA thermograms for Form C respectively.

No weight loss was observed. The material is anhydrous.

In DSC (heating regime: 10 ° C / minute or 20 ° C / minute) an endotherm was observed with a start at plus or minus 134-135 ° C and a peak at plus or minus 137-139 ° C.

Form D

Fig. 13 illustrates a TGA thermogram for Form D.

A total weight loss of 16.6-17.8%, equivalent to plus or minus one mole of MIBK, was observed by TGA either as 1 stage or as 2 stages.

Form E

Fig. 15 illustrates the DSC and TGA thermograms for Form E.

A 16.5% weight / weight loss was observed in TGA associated with 2 endothermic events in DSC recorded at 85 ° C (start) and 151 ° C (start) that could correspond to the

<img file="MX348290B_D0118.tif" />

210 dissolution phenomena.

Example 6: Gravimetric Vapor Absorption of ~ T'GVb) - -

Absorption isotherms were obtained using an SMS DVS Intrinsic moisture absorption analyzer, controlled by DVS Intrinsic Control software vi.0.0.30. Sample temperature was maintained at 25 ° C by instrument controls. Humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml / minute. Relative humidity was measured using a calibrated Rotronic probe (dynamic range 1.0-100% relative humidity), located close to the sample. The weight change, (relaxation of A mass) of the sample as a function of the percentage of relative humidity, was constantly monitored by the microbalance (accuracy ± 0.005 mg). Typically 5-20 mg of the sample was placed in a graduated mesh size stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% relative humidity and 25 ° C (typical ambient conditions). A moisture absorption isotherm was performed as outlined below (2 scans give 1 complete cycle). The normal isotherm was performed at 25 ° C at intervals of 10% relative humidity on a scale of 0-90% relative humidity. Data analysis was performed in Microsoft Excel using DVS Analysis Suite v6.0.0.7. The

<img file="MX348290B_D0119.tif" />

211

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XRPD.

Table 1. Method Parameters for SMS DVS Experiments

Intrinsic

<td>Parameters</td><td>Values</td>

<td>Adsorption - Exploration 1</td><td> 40-90</td>

<td>Desorption / Adsorption - Exploration 2</td><td> 90 - 0,0 - 40</td>

<td>Intervals (% humidity relative)</td><td> 10</td>

<td>Number of scans</td><td> 2</td>

<td>Flow rate (ml / minute)</td><td> 200</td>

<td>Temperature (° C)</td><td> 25</td>

<td>Stability (° C / minute)</td><td> 0,2</td>

<td>Absorption time (hrs)</td><td>6 hours, end time</td>

Form a

The mass change was &lt;0.3% w / w between 0-90% relative humidity. The material is not hygroscopic. No major changes in XRPD were observed after GVS analysis.

Form b

The mass change was 2.3% w / w between 0-90% relative humidity. No hysteresis was observed. No major changes in XRPD were observed after GVS analysis.

Example 7: Aqueous Thermodynamic Solubility

The aqueous solubility was determined by

IMPI INSTITUTO MUICAN. ZlZ DB LA MOHEfAD industriai suspension of sufficient compound in water to give a maximum final concentration of> 10 mg / ml of the free matrix form of the compound. The suspension was equilibrated at 25 ° C for 24 hours and then the pH was measured. The suspension was then filtered through a C glass fiber filter. The filtrate was then diluted by an appropriate factor, eg 101. Quantification was performed by HPLC with reference to a normal solution of approximately 0.25 mg / ml in DMSO. Different volumes of normal, diluted and undiluted sample solutions were injected. Solubility was calculated using the peak areas determined by integrating the peak found at the same retention time as the main peak in normal injection. '

Table 2. HPLC Method Parameters for Solubility Measurements

<img file="MX348290B_D0120.tif" />

<td colspan="4">₂₁₃ IMPI @ ¿I J INSTITUTO MEXICANO Dfc LA ÉtOPJBDAD w »» INDUSTRY!</td><td></td>

<td>Method Type</td><td colspan="3">Reverse phase with elution gradient '</td><td rowspan="16"></td>

<td>Column:</td><td colspan="3">Phenomenex Luna, C18 (2) 5 μm 50 x 4.6 mm</td>

<td>Column Temperature (° C)</td><td colspan="3"> 25</td>

<td>Normal Injections (μΐ):</td><td colspan="3"> 1, 2, 3, 5, 7, 10</td>

<td>Test Injections (μΐ):</td><td colspan="3"> 1, 2, 3, 10, 20, 50</td>

<td>Detection: Wavelength, bandwidth (nm)</td><td colspan="3"> 260, 80</td>

<td>Flow rate (mi / minute):</td><td colspan="3"> 2</td>

<td>Phase A:</td><td colspan="3">0.1% TFA in water</td>

<td>Phase B:</td><td colspan="3">0.085% TFA in acetonitrile</td>

<td rowspan="7">Schedule:</td><td>Time (mins)</td><td>% Phase TO</td><td>% Phase B</td>

<td> 0,0</td><td> 95</td><td> 5</td>

<td> 1,0</td><td> 80</td><td> 20</td>

<td> 2,3</td><td> 5</td><td> 95</td>

<td> 3,3</td><td> 5</td><td> 95</td>

<td> 3,5</td><td> 95</td><td> 5</td>

<td> 4,4</td><td> 95</td><td> 5</td>

The analysis was performed on a series Agilent system

HP1100 equipped with a diode arrangement detector and

<img file="MX348290B_D0121.tif" />

using the ²¹⁴ IMPI software ChemStation vB02.01-SR1 industrial

Table 3 contains the solubility of Form A in aqueous solution at different pH.

Table 3. Solubility of Form A in Aqueous Solution a

Different Ph

<td>pH</td><td>Concentration (mg / mL)</td><td>Found</td>

<td> 1,2</td><td colspan="2"> 1,3</td>

<td> 1,64</td><td colspan="2"> 1,07</td>

<td> 1, 95</td><td colspan="2"> 0,82</td>

<td> 3</td><td colspan="2"> 0,10</td>

<td> 4</td><td colspan="2"> 0,022</td>

<td> 5</td><td colspan="2"> 0,017</td>

<td> 6</td><td colspan="2"> 0,015</td>

<td> 8</td><td colspan="2"> 0,013</td>

<td> 9</td><td colspan="2"> 0,020</td>

<td> 10</td><td colspan="2"> 0,010</td>

The thermodynamic aqueous solubility of Form B at pH 7.42 was determined at 0.0096 mg / ml.

Example 8: Determination of Chemical Purity

HPLC analysis was performed on an Agilent HP1100 / 1200 system equipped with a diode array detector and using Chemstation software according to the method detailed below:

Table 4: Method Parameters

<img file="MX348290B_D0122.tif" />

215

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<td>Method Type</td><td>Reverse phase with gradient elution</td>

<td>Constitution of the test sample:</td><td>Approx. 0.1 mg / ml at 60:40 v / v H₂Or: ACN</td>

<td>Column:</td><td>Gemini-NX C18, 4.6 x 150mm, 3pm</td>

<td>Column temperature (° C):</td><td> 40</td>

<td>Injection (μΐ):</td><td> 100</td>

<td>Detection: Wavelength, bandwidth (nm)</td><td>260, scanning from 210 to 500 nm</td>

<td>Flow rate (ml / minute):</td><td colspan="3"> 1,5</td>

<td>Phase A:</td><td colspan="3">0.1% TFA in water</td>

<td>Phase B:</td><td colspan="3">0.1% TFA in acetonitrile</td>

<td rowspan="9">Schedule:</td><td>Weather (mins)</td><td>% Phase TO</td><td>% Phase B</td>

<td> 0</td><td> 75</td><td> 25</td>

<td> 10</td><td> 70</td><td> 30</td>

<td> 30</td><td> 65</td><td> 35</td>

<td> 45</td><td> 35</td><td> 65</td>

<td> 46</td><td> 10</td><td> 90</td>

<td> 50</td><td> 10</td><td> 90</td>

<td> 51</td><td> 75</td><td> 25</td>

<td> 60</td><td> 75</td><td> 25</td>

²¹⁶ JM PI

INSTITUTE MtXlCANl.

<td>Weather</td><td>from</td><td>retention:</td><td>--- Approx. 20 minutes</td><td>INDUSTRIAL</td>

<td>Washed</td><td>from</td><td>needle:</td><td>Methanol: water (8: 2) -</td><td></td>

In some forms, Form A is more than 95% pure by HPLC analysis. In some forms, Form A is greater than 96% pure by HPLC analysis. In some forms, Form A is more than 97% pure by HPLC analysis. In some forms, Form A is more than 98% pure by HPLC analysis. In some forms, Form A is more than 99% pure by HPLC analysis. In some forms, Form A is 99.8% pure by HPLC analysis. .

In some forms, Form B is more than 95% pure by HPLC analysis. In some forms, Form B is greater than 96% pure by HPLC analysis. In some forms, Form B is more than 97% pure by HPLC analysis. In some forms, Form B is more than 98% pure by HPLC analysis. In some forms, Form B is more than 99% pure by HPLC analysis. In some forms, Form B is 97.8% pure by HPLC analysis. In some forms, Form B is 99.8% pure by HPLC analysis.

In some forms, Form C is more than 95% pure by HPLC analysis. In some forms, Form C is greater than 96% pure by HPLC analysis. In some

217

IMPI rw i *. · Λ⁰'' Γ> - <forms, Form C has more than 97% purity 'M ^ fe / anNC HPLC analysis. In some ways, Form C

98% purity by HPLC analysis. In some forms, Form C is more than 99% pure by HPLC analysis. In some forms, Form C is 99.4% pure by HPLC analysis.

Example 9: Determination of Chiral Purity

The chiral purity of Compound 1 was determined using a Lux Cellulose-1 chiral column by normal phase HPLC. The mobile phase is made up of 20% isopropyl alcohol and 80% hexanes. The enantiomers of 1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) piperidin-l-yl) prop-2 are detected at 260 nm -en-l-one. In one form, compound 1 is dissolved in a mixture of Hexanes: IPA = (7: 3) to obtain a concentration of about 0.2 mg / mL and the chiral purity of the sample is analyzed. The content of the R enantiomer is determined by normalizing the peak area of ​​the enantiomeric ridges and is expressed by weight to weight percent. In some forms, a sample of Compound 1 includes less than 5.0%, less than 4.0%, less than 3.0%, less than 2.0%, or less than 1.0% of the (S) -isomer. . In some forms, a sample of Compound 1 includes less than 1.0% of the (S) -isomer.

Solid Oral Dosage Forms ₂₁₈ IMPIS

MEXICAN INSTITUTE

OF THE CURRENCY ΧΛ ·

In some forms, 1- ((R) -3- (4-WÍW-3 ^ (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-l-ylT plpsridlu · 1-yl ) prop-2-en-l-one as a solid oral dosage form In some forms, the crystallinity of 1 ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH- crystalline pyrazolo [3,4-d] pyrimidin-l-yl) piperidin-l-yl) prop-2-en-l-one in solid oral dosage form. In some forms, it is prepared as tablets 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-l-yl) piperidin-lyl) prop-2-en-l-one crystalline. In some forms, it is prepared as 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-l-yl) piperidin-l- pills. yl) prop-2-en-l-one crystalline. In some forms, 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4— d] pyrimidin-l-yl) piperidin- is prepared as capsules. l-yl) prop-2-en-l-one crystalline. In some forms, 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-yl) piperidin-lyl) prop- 2-en-l-one crystalline in capsules without excipients or with excipients. In any of these forms, 1 - ((R) 3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-lyl) piperidin-l-yl) prop- 2-in-l-one crystalline is Form A. In any of these forms, 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-yl) piperidin-l-yl) prop- Crystalline 2-in-l-one is Form B. In any of these forms the

<img file="MX348290B_D0123.tif" />

piperidin-l-yl) prop-2-en-lo 'pyrazolo [3,4-d] pyrimidin-l-yl) crystalline is Form C. In any of these forms, 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4d] pyrimidin-l-yl) piperidin-l-yl) prop-2-en-l-one crystalline is Form D. In any of these forms, 1 - ((R) -3 (4-amino-3- (4-phenoxyphenyl) -lH-pyrazolo [3,4-d] pyrimidin-l-yl) piperidin-l-yl) prop- 2-in-l-one crystalline is Form E. In any of these forms, 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -IH-pyrazolo [3,4-d] pyrimidin-l-yl) piperidin-lyl) prop-2 -en-l-one crystalline is Form F. In any of these forms, 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine -l-yl) piperidin-l-yl) prop-2-en-l-one crystalline is a mixture of two or more crystalline forms selected from the group consisting of Form A, Form B, Form C, Form D , Form E and Form F.

Example 10: Capsule Preparations

In one form, it is made from the following ingredients to the capsule preparations of Compound 1 for human administration.

Table 5. Capsule Preparations

220 I Μ Ρ I. INSTITUTO MfXICANn \ nt ι a punutriAÍ V &lt;_^Λ

<td rowspan="3">Component</td><td colspan="2" rowspan="2">40 mg capsule</td><td colspan="2" rowspan="2">140 mg capsule</td><td colspan="2">Capsule gives^N140 mg ..</td><td colspan="2">⁰¹or 200 gp.</td>

<td colspan="2"></td><td colspan="2"></td>

<td>or Ό weight/ weight</td><td>mg / capsule</td><td>Q. weight / weight</td><td>mg / capsule</td><td>% weight / weight</td><td>mg / capsule</td><td>g. or weight/ weight</td><td>mg / cap sula</td>

<td>Compound 1 crystalline</td><td> 29, 6</td><td> 40,0</td><td> 60,9</td><td> 140,0</td><td> 42, 4</td><td> 140, 0</td><td> 74,1</td><td> 200,0</td>

<td>Microcrystalline cellulose NF</td><td> 57,4</td><td> 77,5</td><td> 23,0</td><td> 53,0</td><td> 45, 9</td><td> 151, 4</td><td> 8,5</td><td> 23,0</td>

<td>Croscarmellose sodium NF</td><td> 10,0</td><td> 13,5</td><td> 10, 0</td><td> 23,0</td><td> 7,0</td><td> 23,0</td><td> 10,0</td><td> 27,0</td>

<td>Sodium Lauryl Sulfate NF</td><td> 3,0</td><td> 4,0</td><td> 6,1</td><td> 14,0</td><td> 4,2</td><td> 14,0</td><td> 7,4</td><td> 20,0</td>

<td>Stearate magnesium NF</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td> 0,5</td><td> 1, 6</td><td>NA</td><td>NA</td>

In some forms, the manufacturing process includes the following steps: weighing the indicated amount of the components, mixing them together, and adding to an appropriately sized capsule, after which the capsule is closed. In some forms, capsules are stored at room temperature for an extended period until time of use.

Example 11: Immediate Release Tablets

In some forms, tablets are made with the components listed in Table 6.

Table 6 - Components of the Tablet Preparation

<img file="MX348290B_D0124.tif" />

221

IMPI.

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<td>Ingredient</td><td>Scale ___</td>

<td>Compound 1 crystalline</td><td>5% to 50%</td>

<td>Hypromellose</td><td>2% to 10%</td>

<td>Croscarmellose sodium</td><td>0% to 15%</td>

<td>Microcrystalline cellulose</td><td>5% to 50%</td>

<td>Lactose</td><td>10% to 75%</td>

<td>Magnesium stearate</td><td>or \ ° CJ you CAP LO OJ or</td>

<td>Total</td><td>Tablet weight scale: 300mg to 1000mg</td>

The manufacturing process will typically be granulation (dry, wet, or melt) or direct compression.

Example 12: Safety and Tolerability Study of Compound 1 in Chronic Lymphocytic Leukemia

Purpose: The purpose of this study is to establish the safety and ideal dose of Compound 1 administered orally (420 mg / day) in patients with B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma / well-differentiated diffuse lymphocytic lymphoma.

Primary Outcome Measurements: Safety and tolerability of Compound 1 (frequency, severity and

<img file="MX348290B_D0125.tif" />

relationship of adverse events).

Outcome Measurements Secondary to Pharmacokinetic / Pharmacodynamic Assessments. Overall response rate tumor response as defined by recent guidelines on CLL and SLL (B-cell lymphoma) and duration of response.

Eligibility: 18 years and over; both genders are eligible.

Inclusion Criteria: 1) For treatment naive group only: Men and women aged ^ 65 years with a confirmed diagnosis of CLL / SLL, who require treatment according to NCI or International Working Group guidelines 11-14. 2) For relapsing / rebellious group. Men and women ^ 18 years of age with a confirmed diagnosis of relapsing / rebellious CLL / SLL that does not respond to treatment (i.e., ^ 2 previous treatments for CLL / SLL failed and at least 1 regimen had to receive an analog of purine [eg, fludarabine] for CLL subjects). 3) Body weight ^ 40 kgs. 4) ECOG performance condition of &lt;2.5. 5) Agreement to use contraception during the study and for 30 days after the last dose of the study drug in the case of sexually active persons with the possibility of having children. 6) Desire and ability to participate in all²²³evaluations and procedures required in this study protocol, including the ingestion of capsules without dil-LcuH / adi „7) Ability to understand the purpose and risks of the study and to give written, signed and dated consent and authorization to use health information protected (in accordance with the subject's privacy regulations, both national and local).

Exclusion Criteria: 1) A life-threatening disease, medical condition, or organ system dysfunction which, in the opinion of the investigator, could compromise the subject's safety, interfere with the absorption or metabolism of Compound 1 PO, or place undue risk the results of the study. 2) Any immunotherapy, chemotherapy, radiotherapy, or experimental therapy within 4 weeks prior to the first dose of study drug (corticosteroids are allowed for disease-related symptoms but a 1-week purification is required prior to administering study drug ). 3) Complication of the central nervous system (CNS) by lymphoma. 4) Major surgery within 4 weeks prior to the first dose of study drug. 5) Creatinine> 1.5, x Institutional Upper Limit of Normal Value (ULN); total bilirubin> 1.5x ULN (unless due to Gilbert's disease); and aspartate

ΙΜΡΙ ^> 2 2 4 Mexican institute

Say INDUSTRIAL CURRENCY aminotransferase (AST) or alanine aminotransferase (ALT)> 2.5 x ULN unless related to disease. 6) Concomitant use of drugs known to cause QT prolongation or torsades de pointes, 7) Significant electrocardiogram (ECG) abnormalities, including left bundle branch block, type II second-degree AV block, third-degree block , bradycardia and QTc> 470 msec. 8) Lactation or pregnancy.

Example 13: Safety and -Efficacy of Compound 1 in Subjects with Relapsing / Refractory Palio Cell Lymphoma (MCL)

The primary objective of this trial is to evaluate the efficacy of Compound 1 in relapsing / refractory subjects with Palio Cell Lymphoma (MCL). The secondary objective is to evaluate the safety of a fixed daily dose of Compound 1 (560 mg / day in capsule form) in this population.

Primary Outcome Measurements: Measure the number of participants with a response to Compound 1.

Secondary Outcome Measurements: Measure the number of participants with adverse events as a measure of safety and tolerability. Measure pharmacokinetics to help determine how the body responds to the study drug. Results reported by the

225

IMPI

WSTnyro MEXICANO patient (to measure the number of participants who reported results, to determine health-related quality of life).

Eligibility: Individuals 18 years of age and older, of both genders are eligible.

Inclusion Criteria: Men and women of ^ 18 years of age. ECOG performance condition of ^ 2. Pathologically confirmed MCL, with documentation of overexpression of cyclin DI ot (ll; 14) and measurable disease in cross-sectional images that is ^ 2 cm in the longest diameter and measurable in 2 perpendicular dimensions. Documented failure to achieve at least a partial response (PR), or documented progression of disease later, to the most recent treatment regimen. At least 1 but no more than 5 MCL pretreatment regimens. (Note: Subjects who have received ^ 2 previous cycles of bortezomib treatment, either as a single agent or as part of combination therapy, will be considered exposed to bortezomib). Desire and ability to participate in all the evaluations and procedures required in this study protocol, including the ingestion of capsules without difficulty). Ability to understand the purpose and risks of the study and provide signed and dated consent and authorization for the use of protected health information (from

226 IMPIOUS ^m5Tjy2OM £ x_{JCAN (J} according to the privacy regulations of suj '। λΪ a ^^^ r national and local).

Main exclusion criteria: Previous chemotherapy within 3 weeks, nitrosoureas within 6 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy within 3 weeks, or major surgery within 2 weeks from the first dose of study drug. Any life-threatening disease, medical condition, or organ system dysfunction that, in the opinion of the investigator, could compromise the subject's safety, interfere with the absorption or metabolism of Compound 1 capsules, or place the results of the test at undue risk. study. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within six months of classification or any Class 3 or 4 heart disease as defined by the New York Heart Association Functional Classification. Malabsorption syndrome, disease significantly affecting gastrointestinal function or resection of the stomach or small intestine or ulcerative colitis, symptomatic irritable bowel disease, or complete obstruction of the intestine.

Any of the following laboratory abnormalities:

<img file="MX348290B_D0126.tif" />

227

IMPI

INSTITUTO MEXICANO Di LA BR NIELAD INDUSTRIAL

1. Absolute neutrophil count (ANC) (0.75 x 109 / L) unless a bone marrow complication is documented. 2. Platelet count <50,000 cells / mm³(50 x 109 / L) independent of transfusion support, unless there is a documented bone marrow complication. 3. Serum aspartate transaminase (AST / SGOT) or alanine transaminase (ALT / SGPT) ^ 3.0 x upper limit of normal value (ULN). 4. Creatinine> 2.0 x ULN.

Example 14: Phase 2 Study of the Combination of Compound 1 and Rituximab in Patients with Leukemia

High Risk Chronic Lymphocytic Lymphoma and Small Lymphocytic Lymphoma Patients

Purpose: The goal of this clinical research study is to find out if Compound 1 combined with rituximab 15 can help control chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The safety of this combination will be studied.

Rituximab (375 mg / m²) was administered intravenously (IV) on Day 1, Day 8, Day 15 and Day 22 and then 20 was continued once every 4 weeks only on Days 1 during cycles 2-6. Administration of Compound 1 was started on Day 2 of Cycle 1 at a dose of 420 mg (3 x 140 mg capsules) orally daily and will continue daily.

<img file="MX348290B_D0127.tif" />

IMPI

INSTITUTO MEXICANO OE LA PE IMEDA ^ 228 industrial

Primary Outcome Measurements: advancement-free qnpora-ivanria (PFS) [Time: 3 months] - advancement-free survival is defined as the time interval from treatment to progressive disease or death, whichever occurs first. Patients in complete remission (CR), partial remission (PR) or stable disease (SD) are counted as progression-free. Survival or times to advancement functions were estimated using the Kaplan-Meier method.

Secondary Outcome Measurements: Toxicity [Time: 3 months] - toxicity reported by type, frequency and severity. Worst grades of toxicity per patient tabulated for selected adverse events and laboratory measurements. Toxicity (grade 3 or 4) was monitored based on the Bayesian model (beta-binomial), by assuming a priori probability of toxicity after beta (1,1).

Eligibility: 18 years and over; both genders are eligible.

Inclusion Criteria: 1. Patients must have a diagnosis of high-risk CLL / SLL and will be previously treated with up to 3 lines of prior therapy. High-risk CLL and high-risk SLL are defined by the presence of the 17p deletion or llq deletion or TP53 mutation. Any patient with CLL and SLL who has a short duration of

IMPI remission of less than 3 years after prior first-line chemoimmunotherapy, such as FCR regimen, also meets the criteria for high-risk CLL / SLL, regardless of the presence or absence of cytogenetic abnormalities. 2. Patients with CLL and SLL with 17p deletion or TP53 mutation will not be required to have received any prior therapy, given the poor outcome of patients with CLL / SLL to normal first-line chemoimmunotherapy; such patients will be eligible if they are not treated or have received up to 3 lines of prior therapy. 3. Patients must have an indication for treatment according to the 2008 IWCLL Criterion. Four. Patients aged> 18 years at the time of signing the written consent. They understand and voluntarily sign a written consent. They must be able to comply with study procedures and follow-up examinations. 5. ECOG / WHO performance condition of 0-1. 6. Ñps patients with the potential to conceive children should use highly effective birth control (eg, condoms, implants, injectable compounds, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence or sterilized couple) during the study and for 30 days after the last dose of study drug. Women with the potential to conceive include any woman who has undergone menarche and has had satisfactory surgical sterilization (hysterectomy, bilateral tubal ligament, or bilateral oophorectomy) or is not postmenopausal. Post-menopause is defined as follows; Amenorrhea> / = 12 consecutive months with no other cause and a documented level of serum follicle stimulating hormone (FSH)> 35 mlU / mL; a man with the potential to have children is any man who has not been surgically sterilized. Ί. Adequate kidney and liver function 10 as indicated by all of the following:

Total bilirubin </ = 1.5 according to the Institutional Upper Limit (ULN), except for patients with increased bilirubin due to Gilbert's disease, who will be allowed to participate; an ALT </ = 2.5 x ULN; and an estimated creatinine clearance (CrCl) of> 30 mL / minute, as calculated by the Cockroft-Gault equation unless related to disease. 8. Absence of previous malignancies for 3 years, with the exception of basal cell carcinoma, squamous cell of the skin currently treated, or carcinoma in situ of the cervix or breast. 9. A urine pregnancy test (7 days from Day 1) is required for women of childbearing potential.

Criteria

Exclusion: 1.

You are pregnant breastfeeding woman. 2 .

Treatment that includes chemotherapy, AI with monoclonal antibody therapy, radiotherapy high doses of corticosteroids (more than 60 mg of Prednisone or equivalent daily) or immunotherapy at 21 days before recruitment or simultaneously with this test. 3. Investigative agent received 30 days prior to first dose of study drug or who has previously taken Compound 1. If you received any investigational agents before this time, drug-related toxicities must have recovered to Grade 1 or less prior to the first dose of study drug. 4. Systemic infection by fungi, bacteria, viruses or other uncontrolled infection (defined as presenting signs / symptoms in progress, related to the infection and without improvement, despite appropriate antibiotics or other treatment). 5. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune thrombocytopenia (ITP). 6. Patients with severe hematopoietic insufficiency, as defined by an absolute neutrophil count of less than 500 / micro-L and / or a plaguette count of less than 30,000 / micro-L at the time of classification for this protocol. 7. Any other severe concurrent illness or have a history of serious organ dysfunction or disease involving the heart, kidneys, liver or other organ system that may place the patient at undue risk

IMPI ^

INSTITUTO MEXICANO Q no Dt THE PROPERTY

ZjZ INDUSTRIAL -to receive therapy with Compound 1 and rituximab. 8. Major cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within 6 months of classification or any Class 3 or 4 heart disease as defined by the New York Heart Association Functional Classfication. 9. Major ECG abnormalities, including left bundle branch block, type II second-degree AV block, third-degree block, bradycardia, and QTc> 470 msec. 10. any serious medical condition, laboratory abnormality, or psychiatric illness that places the subject at unacceptable risk if they participate in the study. 11. History of stroke or brain hemorrhage within 6 months. 12. Evidence of bleeding diathesis or coagulopathy. 13. Major surgical procedure, open biopsy, or major traumatic injury 28 days prior to Day 1, anticipation of the need for a major surgical procedure during the course of the study. Minor surgical procedures, fine needle aspirations or core biopsies 7 days prior to Day 1. Bone marrow aspiration and / or biopsy is allowed. 15. Unhealed wound, ulcer, or severe bone fracture. 16. Coumadin treatment. Patients who recently received Coumadin should withdraw it at least 7 days before the start of the study. 1-7. Any

TAX M EX ICa N „_ ON PROPERTY C—

233 Industrial chemotherapy (eg, bendamustine, cyclophosphamide, pentostatin, or fludarabine), immunotherapy (eg, alemtuzumab or ofatumumab), bone marrow transplantation, experimental therapy, or radiation therapy are prohibited during therapy in this study. 18. Use of drugs that are known to prolong the QTc interval or that may be associated with Torsades de Pointes (see Appendix F) are prohibited within 7 days of the start of the study drug and during treatment with the study drug.

The examples and forms described herein are illustrative and various modifications or changes suggested by those skilled in the art will be included in this description. As will be appreciated by those skilled in the art, the specific components listed in the above examples can be replaced with other functionally equivalent components, eg diluents, binders, lubricants, fillers, etc.

234

NOVELTY OF ΙΑ INVENTION

IMPI iNOuyrwAi

<img file="MX348290B_D0128.tif" />

Having described the present invention as above, it is considered a novelty and therefore, the content of the following is claimed as property.