NZ723518B2 - Salts and solid form of a btk inhibitor - Google Patents

Abstract

Disclosed herein are processes for preparing Bruton Tyrosine Kinase (BTK) inhibitor 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile free base (compound (I) ), salts of compound (I) and solid state form of said salts. Also disclosed herein are pharmaceutical compositions comprising such salts and solid state form thereof and methods of treating cancer, autoimmune, and inflammatory diseases using compound (I) or a pharmaceutically acceptable salt thereof. lid state form of said salts. Also disclosed herein are pharmaceutical compositions comprising such salts and solid state form thereof and methods of treating cancer, autoimmune, and inflammatory diseases using compound (I) or a pharmaceutically acceptable salt thereof.

Description

(12) Granted patent caon (19) NZ (11) 723518 (13) B2 (47) Publicaon date: 2021.12.24 (54) SALTS AND SOLID FORM OF A BTK INHIBITOR (51) Internaonal Patent Classificaon(s): A61K 31/5395A61P 17/00 (22) Filing date: (73) Owner(s): 2015.02.20 PRINCIPIA BIOPHARMA INC. (23) Complete specificaon filing date: (74) Contact: 2015.02.20 Spruson & Ferguson Pty Ltd (30) Internaonal Priority Data: (72) or(s): US 61/943,262 2014.02.21 MASJEDIZADEH, Mohammad Reza US 61/946,480 2.28 GOURLAY, Steven US ,468 2014.12.23 (86) Internaonal Applicaon No.: (87) Internaonal Publicaon number: WO/2015/127310 (57) Abstract: Disclosed herein are processes for preparing Bruton ne Kinase (BTK) inhibitor 2-[(3R) [4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl] methyl[4-(oxetanyl)piperazinyl]pentenenitrile free base (compound (I) ), salts of compound (I) and solid state form of said salts. Also disclosed herein are pharmaceucal composions comprising such salts and solid state form thereof and methods of treang cancer, autoimmune, and inflammatory es using compound (I) or a pharmaceucally acceptable salt thereof.

NZ 723518 B2 SALTS AND SOLID FORM OF A BTK INHIBITOR Field sed herein are processes for preparing 2-[(3R)[4-amino(2-fluorophenoxy- phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazin yl]pentenenitrile free base (also referred to herein as Compound (I)) having the structure: (I) , certain salts of compound (I) and a solid state form of said salts. The line at the alkene carbon, in compound (I) denotes that compound (I) or a pharmaceutically acceptable salt thereof can be E isomer, Z , or a mixture of (E) and (Z) isomers. Also disclosed herein are pharmaceutical compositions comprising such salts and solid state ) of Compound (I) or a pharmaceutically acceptable salt thereof. Compound (I) and pharmaceutically acceptable salts thereof are potent Bruton Tyrosine Kinase (BTK) inhibitors, and hence can be useful for the ent of diseases such as cancer, autoimmune, and inflammatory diseases.

Background Compound (I) is disclosed in Example 31 of the PCT Application No. PCT/US2013058614 filed on September 6, 2013. The disclosed synthesis es compound (I) requiring purification by column chromatography and affording a foam upon removal of solvent which can be crushed to obtain a powder.

For a compound to be suitable for use as a therapeutic agent, the compound synthesis must be amenable to large scale manufacturing and isolation, and the physical properties of the compound should be such that they do not negatively impact the iveness and cost of a ated active ingredient.

Summary In a first aspect, the present ion provides a method of treating pemphigus vulgaris in a non-human mammal, comprising administering to said man mammal a pharmaceutical composition comprising a compound selected from (E) isomer, (Z) , and a mixture of (E) and (Z) isomers of 2- [(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]- 4-methyl[4-(oxetanyl)piperazinyl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds.

In a second aspect, the present invention provides a method of treating pemphigus vulgaris or pemphigus foliaceus in a non-human mammal in need thereof where corticosteroid therapy is used as the first or second line y comprising administering to said non-human mammal in need of said treatment a eutically effective amount of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2- [(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]-pyrimidinyl]piperidine carbonyl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds in place of or in ation with said corticosteroid therapy; and optionally stering said (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluoro phenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetan yl)piperazinyl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds, in combination with a noncorticosteroidal immunosupressive agent, or an antiinflammatory agent, or both a noncorticosteroidal immunosupressive agent and an antiinflammatory agent.

In a third aspect, the present invention provides a method of treating pemphigus vulgaris or pemphigus foliaceus in a non-human mammal in need thereof where corticosteroid therapy is used as the first or second line maintenance therapy sing administering to said non-human mammal in need of said treatment a therapeutically ive amount of a compound selected from (E) isomer, (Z) , and a mixture of (E) and (Z) isomers of 2- [(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]- 4-methyl[4-(oxetanyl)piperazinyl]pentenenitrile, or a pharmaceutically acceptable salt of any of the foregoing compounds, in place of or in ation with said corticosteroid therapy; and ally administering said (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluoro phenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetan erazinyl]pentenenitrile; or a ceutically acceptable salt of any of the foregoing compounds, in combination with a noncorticosteroidal immunosupressive agent, or an antiinflammatory agent, or both a noncorticosteroidal immunosupressive agent and an antiinflammatory agent.

In a fourth aspect, the present invention es a use of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluorophenoxyphenyl )pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazin yl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds for the manufacture of a medicament for treating pemphigus vulgaris.

In a fifth aspect, the present invention provides a use of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluorophenoxyphenyl )pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazin yl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing nds for the manufacture of a medicament for treating pemphigus vulgaris or pemphigus foliaceus where corticosteroid y is used as the first or second line therapy, wherein said medicament is to be administered in place of or in combination with said corticosteroid therapy; and optionally wherein said ment is to be administered in combination with a noncorticosteroidal immunosupressive agent, or an antiinflammatory agent, or both a noncorticosteroidal supressive agent and an flammatory agent.

In a sixth aspect, the t invention provides a use of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluorophenoxyphenyl )pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazin yl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds, for the manufacture of a medicament for treating pemphigus vulgaris or pemphigus eus where corticosteroid therapy is used as the first or second line maintenance therapy, wherein said medicament is to be administered in place of or in combination with said corticosteroid therapy; and optionally wherein said medicament is to be administered in combination with: a noncorticosteroidal immunosupressive agent, or an antiinflammatory agent, or both a noncorticosteroidal immunosupressive agent and an antiinflammatory agent.

In a seventh aspect, the t invention provides a sulfonic acid or ylic acid salt of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2-[(3R)[4- amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]-pyrimidinyl]piperidinecarbonyl]methyl- 4-[4-(oxetanyl)piperazinyl]pentenenitrile, ably wherein the sulfonic salt or carboxylic acid salt is a mono- or di-methanesulfonic acid salt.

In an eighth aspect, the present invention provides an amorphous form of a pharmaceutically acceptable salt of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]-pyrimidin- 1-yl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile.

In a ninth aspect, the present invention provides a pharmaceutical composition comprising the sulfonic acid or carboxylic acid salt of the seventh aspect or the amorphous form of a ceutically acceptable salt of the eighth aspect.

In a tenth aspect, the present invention provides a method of treating gus vulgaris in a non-human mammal in need of such treatment which method comprises administering to the non-human mammal the pharmaceutical composition of the invention.

In an eleventh , the present invention provides a use of the pharmaceutical composition of the invention for the manufacture of a ment for ng pemphigus vulgaris. 1b followed by page 2 2015/016963 Isolation of compound (I) as described in PCT Application No. PCT/U82013058614 is less than ideal for large scale synthesis and isolation and ore handling and formulating of the resulting nd can present challenges. In addition, when ed as described in PCT Application No. PCT/USZOI3058614, the isolated compound (I) retains a higher percentage of residual solvent after drying under vacuum at ambient temperature than that allowed under the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines ( e. g., — ICH limit for class 2 ts ranges between 50—3880 ppm and for class 3 solvents < 5000 ppm). Due to thermal instability of compound (I), further drying at elevated temperatures cannot be accomplished without the generation of compound (1) related impurities.

Additionally, in a recent pre—clinical study conducted by the Applicant in which a dog suffering from pemphigus foliaceus (PF) was administered 2—(3—(4—amin0—3-(2—fluoro— 4~phenoxy~phenyl)—1H—pyrazolo[3,4~d]pyrimidin—1—yl)piperidine-l-carbonyl)-4,4- dimethylpent—Z—enenitrile, a BTK inhibitor, as a single agent, it was surprisingly discovered that inhibition of BTK is effective and safe for the ent of PF.

It was also surprisingly discoved that the manifestation of pre—clinical response with (R,E)—2—(3—(4—amino—3—(2—fluoro~4~phenoxypheny1)—1H—pyrazolo[3,4—d]—pyrimidin-1— yl)piperidinecarbonyl)—4,4—dimethylpent—Z-enenitrile, was as rapid and comparable to that observed with systemic corticosteroid therapy and none of the well-known corticosteroid-like adverse effects in canines, such as polyuria, polydipsia, polyphagia or weight gain, was observed.

Accordingly, among the various aspects of the present disclosure may be noted the provision of a process for the ion of compound (I) as a free flowing, processable solid, making it amenable to large scale manufacturing and isolation of nd (I). Also provided are certain pharmaceutically acceptable salts of compound (I) and a solid state form of a ceutically able salt of compound (I). The present disclosure also provides methods of treating a blistering disease, such as pemphigus vulgaris (PV) or pemphigus foliaceous (PF) with nd (I) or a pharmaceutically acceptable salt thereof in a mammal, use of compound (I) or a pharmaceutically acceptable salt thereof as a replacement therapy for corticosteroid therapy for diseases treatable with a corticosteroid (such as autoimmune or inflammatory e and in particular where corticosteroids are used as first or second line therapy) where a rapid clinical response is desirable. Also, disclosed are methods of ng automimmune and/or inflammatory diseases with compound (I) or a pharmaceutically acceptable salt thereof at a specific phase of the e process (such as acute phase and/or at onset and duration of an acute flare) and for a limited amount of time so as to maximixe short term relief, minimize long term progression of the disease, and minimize long term toxicological and other e s.

Accordingly, in a first aspect disclosed herein is a sulfonic acid or a carboxylic acid salt of compound (I).

Embodiment (1a) In one embodiment (embodiment (1a)) of the first aspect, the salt is a ic acid salt of compound (I).

Within embodiment (1a), in one embodiment the sufonic acid salt of compound (I) is mono— or di-methanesulfonic acid, mono or di-benezenesulfonic acid, mono— or di- toluenesulfonic acid, or ethane—1,2—disulfonic acid salt of compound (I). Within embodiment (1a), in another embodiment the sufonic acid salt of compound (I) is mono— or di— methanesulfonic acid salt of compound (I). Within embodiment (1a), in yet another embodiment the sufonic acid salt of compound (I) is di- methanesulfonic acid salt of compound (1). Within embodiment (1a), in another embodiment the sufonic acid salt of compound (I) is mono methanesulfonic acid salt of compound (I).

Embodiment t 1b! In another embodiment (embodiment (1b)) of the first aspect, the salt is a carboxylic acid salt of compound (I).

Within embodiment (1b), in one embodiment the carboxylic acid salt of compound (I) is c acid, oxalic acid, tartaric acid, maleic acid, citric acid, or malonic acid salt of nd (I).

In a second aspect, disclosed herein is an amorphous form of a pharmaceutically able salt of compound (I).

Embodiment (2a) In one embodiment (embodiment (2a)) of the second aspect, the amorphous form is of a ic acid salt of compound (1).

Within embodiment (2a), in one embodiment the amorphous form is of mono- or di- esulfonic acid, mono or di-benezenesulfonic acid, mono— or di—toluenesulfonic acid, or ethane-1,2—disulfonic acid salt of compound (1). Within embodiment (2a), in another embodiment, the amorphous form is of mono— or di-methanesulfonic acid salt of compound (1). Within embodiment (2a), in another embodiment the c acid salt is the dimethanesulfonic acid salt of compound (I). Within embodiment (2a), in r embodiment the sufonic acid salt is the mono methanesulfonic acid salt of compound (I).

WO 27310 Embodiment (2b) In another ment (embodiment (2b)) of the second aspect, the amorphous form is of a carboxylic acid of compound (I).

Within embodiment (2b), in one embodiment, the amorphous form is of c acid, oxalic acid, tartaric acid, maleic acid, citric acid, or malonic acid salt of compound (I).

Embodiment (2c) In yet another ment (embodiment (2c)) of the second aspect, in embodiments (2a) and (2b) and embodiments contained therein, the amorphous form of any of the aforementioned salts of compound (I) is substantially free of any crystalline form(s) thereof.

Within embodiment (2c), in one embodiment, at least about 80% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (2c), in r embodiment at least about 85% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (2c), in yet another embodiment, at least about 90% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (2c), in yet another embodiment, at least about 95% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (2c), in yet r embodiment, at least about 98% wiw of any of the aforementioned salts of compound (I) is in the amorphous form. Within (2c), in yet another embodiment, at least about 99% w/w of any of the entioned salts of compound (I) is in the amorphous form.

Embodiment (31 In yet another embodiment (embodiment (3)) of the first aspect, the second aspect, and embodiments contained therein (i.e., (1a), (lb), (2a), (2b), and (20) and embodiments contained therein), the salt or amorphous form of the salt of compound (I) is a substantially pure (E) or ntially pure (Z) isomer of compound (1).

Within embodiment (3), in one embodiment at least about 80% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 80% w/w of the salt of compound (I) or the amorphous form of the salt of nd (I) is the Z isomer of compound (I). Within embodiment (3), in another embodiment at least about 85% w/w of the salt of compound (I) or the ous form of the salt of compound (I) is the E isomer of compound (I) or at least about 85% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (I). Within embodiment (3), in another embodiment, at least about 90% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 90% w/w of the salt of nd (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (1). Within embodiment (3), in yet another embodiment, at least about 95% w/w of the salt of nd (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 95% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (1). Within embodiment (3), in yet another embodiment, at least about 96% w/w of the salt of nd (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 96% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (1). Within embodiment (3), in yet another ment, at least about 97% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 97% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (1). Within embodiment (3), in yet another embodiment, at least about 99% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of nd (I) or at least about 99% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the Z isomer of nd (I). The ratio of the E to Z isomer can be calculated by methods well known in the art. One such method is HPLC total area normalization method.

In a third aspect, disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of any of the salts of compound (I) or an amorphous form of any of the salts of compound (I) disclosed in the first, the second aspect, embodiments contained in the first or second aspect (i.e., (la), (1b,) (2a), (2b), (2c) including any embodiments disclosed therein), or embodiment (3) (including any embodiments disclosed therein), and a ceutically acceptable excipient.

Embodiment (4a) In one embodiment (embodiment (4a)) of the third aspect, the ceutical composition is a solid. Within this ment, in one embodiment the solid formulation is a tablet, capsule or another unit dosage form suitable for oral administration to a mammal. ment 1 4b2 In another embodiment (embodiment (4b)) of the third aspect, the pharmaceutical composition is an emulsion. ment (4c) In yet another embodiment (embodiment (4c)) of the third aspect, the pharmaceutical compostion is a solution.

In a fourth aspect, provided is a process for making an amorphous form of compound (1) comprising: (i) adding an isopropylacetate solution of compound (I) to an antisolvent; (ii) removing the solvent.

In one embodiment of the fourth aspect, the antisolvent is a non-polar hydrocarbon solvent. In another embodiment of the fourth aspect, the antisolvent is heptane.

In a fifth aspect, provided is a process for making an amorphous form of a pharmaceutically able salt of compound (1) comprising: (i) adding a on of a pharmaceutically acceptable salt of compound (I) to an antisolvent; and (ii) ng the solvent. ment {5a) In one embodiment (embodiment (5a)) of the fifth aspect, the amorphous form is of a sulfonic acid salt of compound (I).

Within embodiment (5a), in one ment, the ic acid salt of compound (I) is mono— or di—methanesulfonic acid, mono or ezenesulfonic acid, mono— or di- toluenesulfonic acid, or ethane—1,2—disulf0nic acid salt of compound (1). Within embodiment (5a), in another embodiment, the c acid salt of compound (I) is mono— or di— methanesulfonic acid salt of compound (I). Within embodiment (Sa), in another embodiment the sufonic acid salt of compound (I) is the anesulfonic acid salt of compound (I).

Within embodiment (5a), in another embodiment the sufonic acid salt of compound (I) is mono methanesulfonic acid salt of compound (I).

Embodiment g5b) In another ment (embodiment (5b)) of the fifth aspect, the amorphous form is of a carboxylic acid of compound (1).

Within embodiment (5b), in one embodiment the carboxylic acid salt of compound (I) is fumaric acid, oxalic acid, tartaric acid, maleic acid, or malonic salt salt of compound (I).

Embodiment 1501 In yet another embodiment (embodiment (5c)) of the fifth aspect, in embodiment (5a) and (5b) and embodiments contained therein the amorphous form of any of the aforementioned salt of compound (I) is substantially free of any crystalline form(s) thereof.

Within (Sc), at least about 80% W/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (5c), in another embodiment at least about 85% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (5c), in yet another ment, at least about 90% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (So), in yet another embodiment, at least about 95% w/w of any of the aforementioned salts of compound (I) is in the amorphous form.

Within (5c), in yet another embodiment, at least about 98% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (5c), in yet another embodiment, at least about 99% w/w of any of the aforementioned salts of compound (I) is in the amorphous form.

Embodiment 6 In yet another ment (embodiment (6)) of the fifth aspect and embodiments contained therein (i.e., (5a), (5b), (Sc) and and embodiments contained therein), the amorphous form of the salt of compound (I) is a ntially pure (E) or substantially pure (Z) isomer of compound (1).

Within ment 6, in one embodiment at least about 80% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 80% W/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (I). Within embodiment 6, in another embodiment at least about 85% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 85% w/w of the salt of nd (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (I). Within embodiment 6, in another embodiment, at least about 90% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 90% w/w of the salt of compound (I) or the ous form of the salt of compound (I) is the Z isomer of compound (1). Within embodiment 6, in yet another embodiment, at least about 95% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 95% w/w of the salt of compound (I) or the ous form of the salt of compound (I) is the Z isomer of compound (I). Within embodiment 6, in yet r embodiment, at least about 96% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 96% w/w of the salt of compound (I) or the ous form of the salt of compound (I) is the Z isomer of compound (I). Within embodiment 6, in yet r embodiment, at least about 97% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 97% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (I). Within embodiment 6, in yet another embodiment, at least about 99% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of nd (I) or at least about 99% wiw of the salt of nd (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (I). The ratio of the E to Z isomer can be calculated by methods well know in the art. One such method is HPLC total area normalization method, In a sixth aspect, provided is a method of treating an autoimmune disease, an inflammatory disease, or cancer in a mammal (e.g., human) in need to such ent which method comprises administering to the mammal, a pharmaceutical composition comprising a sulfonic acid or a ylic acid salt of compound (I).

Embodiment (7a) In one embodiment iment (7a)) of the sixth aspect, the pharmaceutical ition comprises a sulfonic acid salt of compound (I).

Within embodiment (7a), in one embodiment, the sufonic acid salt of compound (I) is mono» or di-methanesulfonic acid, mono or di~benezenesulfonic acid, mono- or di~ toluenesulfonic acid, or ethane-1,2—disulfonic acid salt of compound (1). Within embodiment (7a), in another embodiment, the sufonic acid salt of compound (I) is mono- or di~ methanesulfonic acid salt of compound (I). Within embodiment (7a), in another embodiment the sufonic acid of compound (I) is the dimethanesulfonic acid salt of compound (1). Within ment (7a), in another embodiment the sufonic acid salt of compound (I) is mono esulfonic acid salt of compound (I).

Embodiment 17b) In another embodiment (embodiment (7b)) of the sixth aspect, the pharmaceutical composition comprises a carboxylic acid salt of compound (1).

Within embodiment (7b), in one embodiment the ylic acid salt is fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, or c acid salt of compound (I).

In a seventh aspect, ed is a method of treating a autoimmune disease, an inflammatory disease, or cancer in a mammal (e.g., human) in need to such treatment which method comprises administering to the mammal, a pharmaceutical composition comprising an amorphous form of a pharmaceutically acceptable salt of compound (I).

Embodiment (8a) In one embodiment (embodiment (8a)) of the seventh aspect, the amorphous form is of a sulfonic acid salt of compound (1).

Within embodiment (8a), in one embodiment the amorphous form is of mono- or di— esulfonic acid, mono or di-benezenesulfonic acid, mono- or di-toluenesulfonic acid, or -1,2-disulfonic acid salt of compound (I). Within embodiment (8a), in another embodiment, the amorphous form is of mono— or di—methanesulfonic acid salt of compound (I).

Embodiment (8b) In another embodiment (embodiment (8b)) of the seventh aspect, the ous form is of is a carboxylic acid of compound (I). Within embodiment (8b), in one embodiment, the amorphous form is of fumaric acid, oxalic acid, ic acid, maleic acid, or malonic salt salt of compound (I).

Embodiment t8c) In yet another embodiment iment (8c)) of the seventh aspect, embodiments (8a) and (8b) and embodiments ned therein the amorphous form of any of the aforementioned salt of compound (I) is substantially free of any crystalline form(s) thereof.

Within (80), in one ment, at least about 80% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (8c), in another embodiment at least about 85% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (8c), in yet another ment, at least about 90% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (Sc), in yet another embodiment, at least about 95% w/w of any of the aforementioned salts of compound (I) is in the amorphous form. Within (8c), in yet another embodiment, at least about 98% w/w of any of the aforementioned salts of compound (I) is in the ous form. Within (8c), in yet r embodiment, at least about 99% w/w of any of the aforementioned salts of compound (I) is in the amorphous form.

Embodiment 8d In another embodiment (embodiment (8d)) of the sixth aspect, seventh aspect, and embodiments contained therein (i.e., (7a), (7b), (8a), (8b), (8c) and embodiments contained therein), the salt of compound (I) or an amorphous form of the salt of compound (I) is a substantially pure (E) or substantially pure (Z) isomer of compound (1).

Within embodiment (8d), in one embodiment at least about 80% w/w of the salt of nd (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 80% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (I). Within embodiment (8d), in another embodiment at least about 85% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 85% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (I). Within embodiment (8d), in another ment, at least about 90% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 90% w/w of the salt of compound (I) or the ous form of the salt of compound (I) is the Z isomer of compound (I). Within embodiment (8d), in yet another embodiment, at least about 95% w/w of the salt of compound (I) or the ous form of the salt of compound (I) is the E isomer of compound (I) or at least about 95% w/w of the salt of compound (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (1). Within embodiment (8d), in yet another embodiment, at least about 96% w/w of the salt of compound (I) or the amorphous form of the salt of nd (I) is the E isomer of compound (I) or at least about 96% wiw of the salt of nd (I) or the amorphous form of the salt of compound (I) is the Z isomer of compound (1). Within embodiment (8d), in yet another embodiment, at least about 97% wiw of the salt of compound (I) or the amorphous form of the salt of compound (I) is the E isomer of compound (I) or at least about 97% w/w of the salt of compound (I) or the amorphous form of the salt of nd (I) is the Z isomer of nd (I). Within embodiment (8d), in yet another embodiment, at least about 99% w/w of the salt of compound (I) or the amorphous form of the salt of nd (I) is the E isomer of compound (I) or at least about 99% w/w of the salt of compound (I) or the amorphous form of the salt of nd (I) is the Z isomer of compound (I). The ratio of the E to Z isomer can be calculated by methods well known in the art. One such method is HPLC total area ization method.

In one embodiment of the sixth and seventh aspects and embodiments contained therein (i.e,, 7a, 7b, 8a 8b Sc, and 8d and ments contained therein), the mammal in need or recognized need is ing from an autoimmune disease, e.g., thrombotic thrombocytopenic purpura, polyarteritis nodosa, cutaneous lupus, cutaneous form of systemic sclerosis(CREST), systemic sclerosis, mixed connective tissue disease, cryoglobulinemia, primary biliary sclerosis, sclerosing cholangitis, AI urticaria, IgA nephropathy, inflammatory bowel disease, such as ulcerative colitis, arthritis, lupus including Lupus Nephritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still‘s disease, juvenile arthritis, diabetes, myasthenia gravis, granulomatosis with polyangiitis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves’ e, n's syndrome, Sjogren’s dry eye, non-Sjogren’s dry eye disease, multiple sclerosis, Guillain—Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody me, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, su's arteritis, temporal arteritis, mune hemolytic anemia, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, yotonia, scleroderma, pemphigus vulgaris, and vulvodynia. In one embodiment, the e is rheumatoid arthritis or psoriatic arthritis. In another embodiment, the autoimmune disease is lupus, pemphigus vulgaris, granulomatosis with polyangiitis, or rheumatoid arthritis.

In another embodiment of the sixth and seventh aspects and embodiments contained therein, the mammal in need or recognized need is suffering from a heteroimmune condition or disease, e.g., graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

In yet another embodiment of the sixth and seventh aspects and embodiments contained therein (i.e., 7a, 7b, 8a 8b 8c, and 8d and embodiments ned therein), the mammal in need or ized need is suffering from an atory e, e.g., , appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, itis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, enitis suppurativa, laryngitis, mastitis, meningitis, myelitis ditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, tis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, itis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis, preferably asthma or uveitis.

In yet another embodiment disclosed herein, the mammal in need or recognized need is ing from inflammatory skin disease, such as dermatitis, contact dermatitis, eczema, urticaria, a, and scarring psoriatic lesions in the skin, joints, or other tissues or organs.

In yet another embodiment of the sixth and seventh aspects and embodiments contained therein (i.e., 7a, 7b, 8a 8b 80, and 8d and embodiments contained therein), the mammal in need or recognized need is suffering from a cancer. In one embodiment, the cancer is a B-cell proliferative er, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma (CLL), chronic lymphocytic leukemia, chromic enous leukemia, B—ALL, Philadelphia chromosome positive B—ALL,B-cell prolymphocytic ia, small lymphocytic lymphoma (SLL), multiple myeloma, B-cell non~Hodgkin lymphoma, lymphoplamascytic lymphoma/ Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell a, plasmacytoma, extranodal marginal WO 27310 zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell ma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In yet another ment the sixth and seventh aspects and embodiments contained therein (i.e., 7a, 7b, 8a 8b 8c, and 8d and embodiments contained therein), the mammal in need or recognized need is suffering from a thromboembolic disorder, e.g., myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after oronary , osis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, and deep venous thrombosis.

The disclosure is also directed to the ic and ylic acid salts of compound (I) disclosed in the first aspect, an amorphous form of a pharmaceutically acceptable salt of compound (I) disclosed in the second aspect and any of the embodiments thereof disclosed above for use as a medicament. In one embodiment, the use is for treating a disease disclosed above.

The sure is also directed to the use of the sulfonic and carboxylic acid salts of compound (I) disclosed in the first aspect, or an amorphous form of a pharmaceutically acceptable salts of compound (I) (including the ic and carboxylic acid salts of compound (1)) disclosed in the second aspect or any of the embodiments thereof disclosed above in the manufacture of a medicament for treating a disease disclosed above.

In any of the aforementioned embodiments sed herein involving the ent of cancer, combination therapy can be used, i.e., the sulfonic and carboxylic acid salts of compound (I) or an amorphous form of a salt of compound (I) or any of the embodiments thereof disclosed herein can be administered in combination with at least one additional antiproliferative and/or anticancer agent. In one embodiment, the at least additional agent is chosen from alemtuzumab, arsenic trioxide, asparaginase (pegylated or non-), bevacizumab, cetuximab, platinum—based compounds, such as cisplatin, cladribine, daunorubicin/ doxorubicin /idarubicin, irinotecan, fludarabine, 5—fluorouracil, gemtuzamab, methotrexate, paclitaxel, M, docetaxol, temozolomide, thioguanine, and classes of drugs including hormones (an antiestrogen, an antiandrogen, or gonadotropin releasing e ues, interferons such as alpha eron, nitrogen mustards such as busulfan or melphalan or mechlorethamine, retinoids such as tretinoin, topoisomerase inhibitors such as irinotecan or topotecan, tyrosine kinase inhibitors such as gefinitinib or imatinib, ofatumumab, bendamustine, rituximab, obinutuzumab, 5, GS-1101, BKM-IZO, GDC-O941, DGDC- WO 27310 0980, GS-9820, CAL—263, Revlimid®, thalidomide®, pomalidomide®, Velcade ®, Kyprolis ®, delanzomib, U0126, PD98059, PD184352, PD0325901, ARRY—142886, SB239063, SP600125, BAY 43—9006, wortmannin, Nexavar®, Tarceva®, Sutent®, Tykerb®, Sprycel®, Crizotinib, i®, 0r LY294002or agents to treat signs or symptoms induced by such therapy ing rinol, filgrastim, granisetron/ondansetron/ setron, dronabinol When combination therapy is used, the agents can be stered simultaneously or sequentially.

In an eighth aspect, provided is an amorphous form of mono—methanesulfonic or di- esulfonic salt of about 9:1 mixture of (E) isomer of compound (I), which are terized by XRPD (X-ray Powder Diffraction) profile substantially in accoradance with Figures 4A and 4 respectively.

In a ninth aspect, provided is a method of treating thrombotic thrombocytopenic purpura, polyarteritis nodosa, cutaneous lupus, cutaneous form of systemic sclerosis (CREST), systemic sclerosis, mixed connective tissue disease, cryoglobulinemia, primary biliary sclerosis, sclerosing cholangitis, AI ria, IgA nephropathy, Lupus Nephritis, autoimmune hemolytic anemia, granulomatosis with polyangiitis, or pemphigus vulgaris, in a mammal, comprising stering to said mammal a pharmaceutical composition comprising an (E) isomer, (Z) isomer, or a e of (E) and (Z) isomer of 2—[(3R)—3~[4— amino(2-fluoro—4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]- 4~methyl—4—[4—(oxetan—3-yl)piperazin~1~yl]pent-2—enenitrile; or a pharmaceutically acceptable salt of any of the ing compounds.

In one embodiment, the disease is Lupus Nephritis, autoimmune tic anemia, granulomatosis with polyangiitis, or pemphigus vulgaris.

Embodiment 9 In a first embodiment (embodiment 9) of the method of the ninth aspect and ment contained therein, the pharmaceutical composition comprises a substantially pure (E) or (Z) isomer of 2—[(3R)—3—[4—amino(2—fluor0phenoxy—phenyl)pyrazolo[3,4- d]pyrimidin— l —yl]piperidine— 1 —carbonyl] methy1—4—[4—(oxetanyl)piperazinyl]pent—2- enenitrile or a pharmaceutically acceptable salt thereof and the mammal is a human.

Within embodiment (9) of the ninth aspect, in a first embodiment, at least about 85% w/w of 2—[(3R)—3—[4-amino—3-(2—fluoro—4—phenoxy—phenyl)pyrazolo[3,4—d]pyrimidin—1— yl]piperidine—l—carbonyl]-4—methyl-4—[4-(oxetanyl)piperazin—1-yl]pentenenitrile; or at least about 85% w/w of a pharmaceutically acceptable salt thereof is the (E) isomer.

Within embodiment (9), in a second embodiment, at least about 90% w/w of 2-[(3R)- 3-[4-amino—3-(2—fluoro—4—phenoxy—phenyl)pyrazolo[3 ,4-d]pyrimidin- l —yl]piperidine- 1 — carbonyl]~4—methyl—4-[4-(oxetanyl)piperazin—1-yl]pent-2—enenitrile; or at least about 90% wi'w of a ceutically acceptable salt thereof is the (E) isomer.

Within embodiment (9) in a third embodiment, at least about 95% w/w of 2—[(3R)~3- [4-amino(2-fluoro-4—phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin— l -yl]piperidine— 1- carbonyl]—4—methyl—4—[4—(oxetan-3—yl)piperazin~1-yl]pent-2—enenitrile; or at least about 95% w/w of a ceutically acceptable salt thereof is the (E) isomer.

Within embodiment (9) and embodiments contained therein, in one embodiment the disease is gus is and the pharmaceutical composition comprising (E) isomer, (Z) isomer, a mixture of (E) and (Z) isomers, substantially pure (E) or (Z) isomers, or a mixture of (E) and (Z) isomers containing 85%, or 90%, or 95% w/w of E isomer or a mixture of (E) and (Z) isomers containing 85%, or 90%, or 95% w/w of Z isomer of )— 3—[4—amino-3—(2—fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidine-l— carbonyl]-4—methyl—4-[4-(oxetan-3—yl)piperazin—1-yl]pent—2—enenitrile or a pharmaceutically able salt thereof is optionally administered in combination with an immunosuppressive agent chosen from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, enolate l, methotrexate, dapsone, alazine, azathioprine, an anti~CD20 agent (such as rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar version thereof), NFalpha agent (such as entanercept, imab, golilumab, adalimumab, 0r certolizumab pegol or a biosimilar version thereof), anti-1L6 agent toward ligand or its receptors (such as tocilizumab, sarilumab, olokizumab, elsililumab, or siltuximab), L17 agent to ligand or its receptors (such as secukinumab, ustekinumab, brodalumab, or ixekizumab), anti—IL] agent to ligand or its receptors (such as with rilonacept, canakinumab, or anakinra), anti—1L2 agent to ligand or its receptors (such as basiliximab or daclizumab), anti-CD2 agent such as alefacept, anti—CD3 agent such as muromonab-cd3, anti-CD80/86 agent such as abatacept or belatacept, anti-sphingosine—1—phosphate receptor agent such as fingolimod, anti—C5 agent such as eculizumab, anti—integrin alpha4 agent such as natalizumab, anti— (1457 agent such as vedolizumab, anti—mTOR agent such as sirolimus 0r everolimus, anti-calcineurin agent such as tacrolimus, or anti—BAFFfBlyS agent (such as belimumab, VAY736, or blisibimod), leflunomide and teriflunomide. Preferably, the pharmaceutical ition comprising (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomers, substantially pure (E) or (Z) isomer, or a mixture of (E) and (Z) isomers ning 85%, or 90%, or 95% w/w ofE isomer, or a mixture of (E) and (Z) isomers containing 85%, or 90%, or 95% w/w of Z isomer of 2-[(3R)—3—[4—amino-3—(2-flu0rophenoxy- phenyl)pyrazolo[3,4—d]pyrimidin— 1 -yl]piperidinecarbonyl]-4—methyl[4—(oxetan—3— erazin-1—yl]pent—2-enenitrile or a pharmaceutically acceptable salt thereof is optionally administered with rituximab, ofatumumab, obinutuzumab, or umab, or a biosimilar version thereof.

In a tenth aspect, ed is a method of treating an acute inflammatory andIor autoimmune disease in a mammal in need thereof where corticosteroid therapy is used as the first or second line y sing administering to said mammal in need of said treatment a therapeutically effective amount of an (E) isomer, (Z) , or a mixture of (E) and (Z) isomer of 2-[(3R)[4—amino—3-(2—fluoro-4—phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin—1—yl]piperidine-1~carbonyl]~4—methyl—4-[4—(oxetan-3—yl)piperazinyl]pent—2- enenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds in place of or in combination with said corticosteroid y; and optionally administering said (E) isomer, (Z) isomer, or a e of (E) and (Z) isomer of 2-[(3R)[4—amino-3—(2—fluorophenoxy-phenyl)pyrazolo[3,4—d]pyrimidin—1- yl]piperidine~1—Carbonyl]—4—methyl—4—[4—(oxetan-3~yl)piperazin~1—yl]pent—2—enenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds in combination with a noncorticosteroidal supressive and/or antiinflammatory agents.

In an eleventh aspect, provided is a method of treating an inflammatory and/or autoimmune e in a mammal in need thereof where corticosteroid therapy is used as the first or second line maintenance therapy comprising administering to said mammal in need of said treatment a therapeutically effective amount of (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomer of 2-[(3R)—3-[4—amino—3-(2—fluoro-4—phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin—1—y1]piperidine—1-carbonyl]-4—methyl—4—[4-(oxetan—3—yl)piperazin—1-yl]pent-2— enenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds in place of or in combination with said corticosteroid therapy; and optionally administering said (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomer of 2~[(3R)—3—[4—amino-3—(2—fluoro—4—phen0xy-phenyl)pyrazolo[3,4—d]pyrimidin- 1 ~ yl]piperidine— 1 —carbonyl]—4—methyl—4—[4—(oxetan—3—yl)piperazin— 1 ~yl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing nds in combination with a noncorticosteroidal immunosupressive and/or antiinflammatory agent.

In a twelfth aspect, provided is a method of eliminating or reducing a therapeutic dose of corticosteroid used in Chronic maintenance therapy of an inflammatory and/or autoimmune disease in a mammal in need thereof where corticosteroid therapy is used as the first or second line comprising stering to said mammal in need of said treatment a therapeutically effective amount of (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomer of 2—[(3R)-3—[4—amino—3-(2—fluoro—4—phenoxy—phenyl)pyrazolo[3,4-d]pyrimidin—1- yl]piperidine-1 -carbonyl]methyl[4-(oxetan—3-yl)piperazinyl]pent—2-enenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds in place of or in combination with said corticosteroid chronic maintenance y; and optionally administering said (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomer of 2~[(3R)[4-amino—3-(2—fluorophenoxy-phenyl)pyrazolo[3,4—d]pyrimidin yl]piperidine- 1 —carbonyl]—4-methyl-4~[4—(oxetan-3~yl)piperazin~1—yl]pent—2—enenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds in combination with a noncorticosteroidal, supressive, and/or antiinflammatory agents, In a thirteenth aspect, provided is a method of treating acute flares of an autoimmune and/0r inflammatory disease in a mammal in need thereof which method comprises administering to the mammal in need of said treatment a eutically effective amount of (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomer of 2-[(3R)—3—[4—amin0—3—(2—flu0ro— 4~phenoxy~phenyl)pyrazolo[3,4—d]pyrimidinyl]piperidine— l -carbonyl]—4—methyl-4—[4— n—3-yl)piperazin—1—yl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds for a treatment period sufficient to treat acute flares of the autoimmune disease. In one embodiment of the thirteenth ,the said (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomer of )-3—[4-amino-3—(2-fluorophenoxy- phenyl)pyrazolo[3,4—d]pyrimidin-l-y1]piperidine-l-carbonyl]—4—methyl[4-(oxetan-3— yl)piperazin—1—y1]pent-2—enenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds is used instead of corticosteroid therapy where corticosteroid therapy is normally used as the first or second line to treat flares.

Embodiment (10) In a first embodiment (embodiment 10) of the tenth and thirteenth aspects, the acute autoimmune and/or inflammatory disease or the acute flares of an autoimmune and/or an inflammatory disease treatable by a pharmaceutical ition comprising (E) isomer, (Z) , or a mixture of (E) and (Z) isomer of 2-[(3R)[4-amino-3—(2—fluoro—4-phenoxy~ phenyl)pyrazolo[3,4-d]pyrimidin—1—yl]piperidine—l-Carbonyl]—4-methyl[4—(oxetan—3- yl)piperazin—1-yl]pent—2-enenitrile; or a pharmaceutically able salt of any of the foregoing compounds, is chosen from Table (I): Table (I) Acute indications for corticosteroid s of B cell therapy if known them; y Initial presentations or flares of rheumatic Rituximab takes 4-12 weeks to take effect in ers such as tic arthritis, rheumatoid arthritis (ref Rituxan US label) rheumatoid arthritis, ankylosing spondylitis, bursitis, tenosynovitis, gout, synovitis of rthritis, epicondylitis Initial presentation or flares of collagen Rituximab has delayed effect in ANCA— disease such as systemic lupus erythematosus associated vasculitis and achieves remission (SLE), dermato/polymyositis, rheumatic in only 64% of cases despite concomitant use carditis, vasculitis of corticosteroids for 5 months (Stone et al. 2010).

Belimumab, an anti—Blys dy, has a modest and delayed effect on improvement of chronic SLE ing the ability to reduce corticosteroid use to <7.5mg of prednisone at week 40-52 in no more than 21% of patients sta US Product Information).

Initial tations or flares of dermatologic Rituximab has delayed effect in pemphigus diseases such as pemphigus, Stevens-Johnson vulgaris with maximal effect at 8—12 weeks syndrome, exfoliative itis, mycosis (Lundardon & Payne 2012) fungoides, severe psoriasis, severe seborrheic dermatitis Control of incapacitating allergic reactions including asthma, contact or atopic dermatitis, serum sickness, drug hypersensitivity Initial presentations or flares of ophthalmic diseases including allergic corneal ulcers, herpes zoster of the eye, anterior or posterior inflammation/uveitis or choroiditis, sympathetic ophthalmia, allergic conjunctivitis, tis, chorioretinitis, optic is, iritis, iridocyclitis Initial presentations or flares of respiratory diseases including symptomatic sarcoidosis, Loeffler’s syndrome, berylliosis, fulminating or inated tuberculosis, aspiration pneumonitis Initial presentations or flares of hematologic disorders including idiopathic thrombocytopenic purpura, secondary thrombocytopenia, autoimmune tic anemia, erythroblastopenia, congential hypoplastic anemia Acute nephrotic syndrome of SLE Initial presentations or flares of gastrointestinal disease such as ulcerative colitis, Crohn’s disease Acute neurological trauma to reduce swelling Embodiment g 11 1 In an embodiment (embodiment 11) of the tenth, eleventh, twelfth, and thirteenth aspects, the autoimmune and/0r inflammatory disease is chosen from indications where Prednisone is used as a therapeutic agent (see product label).

Prednisone tablets and solutions are indicated in the following conditions: Endocrine Disorders: y or secondary cortical insufficiency (hydrocortisone or cortisone is the first choice: synthetic analogs may be used in ction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance); congenital adrenal hyperplasia; nonsuppurative thyroiditis; hypercalcemia ated with cancer.

Rheumatic Disorders: As adj e therapy for short—term stration (to tide the patient over an acute episode or bation) in: psoriatic tis, rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low—dose maintenance therapy), sing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis, post-traumatic osteoarthritis, synovitis of rthritis, epicondylitis.

Collagen Diseases: During an exacerbation or as maintenance therapy in ed cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis), acute rheumatic carditis.

Dermatologic Diseases: Pemphigus; bullous dermatitis herpetiformis; severe erythema multiforme (Stevens-Johnson syndrome); exfoliative itis; mycosis fungoides; severe psoriasis; severe seborrheic dermatitis. -18..

Allergic States: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: seasonal or perennial ic rhinitis; bronchial asthma; contact dermatitis; atopic dermatitis; serum sickness; drug hypersensitivity reactions. lmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: allergic corneal marginal , herpes zoster ophthalmicus, anterior segment inflammation, diffuse posterior uveitis and choroiditis, sympathetic ophthalmia, allergic conjunctivitis, keratitis, chorioretinitis, optic neuritis, iritis and iridocyclitis.

Respiratory Diseases: Symptomatic sarcoidosis; Loeffler’s syndrome not able by other means; berylliosis; tion pneumonitis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy Hematologic ers: Idiopathic ocytopenic purpura in adults; secondary thrombocytopenia in adults; acquired (autoimmune) hemolytic anemia; erythroblastopenia (RBC anemia); congenital (erythroid) hypoplastic anemia.

Neoplastic Diseases: For palliative management of: leukemias and lymphomas in adults, acute leukemia of childhood. ous States: To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.

Gastrointestinal Diseases: To tide the patient over a critical period of the disease in: ulcerative s, regional enteritis.

Miscellaneous: Tuberculous meningitis with subarachnoid block or impending block when used rently with appropriate antituberculous herapy; nosis with neurologic or myocardial involvement.

Embodiment 1 121 In a second embodiment (embodiment 12) of the tenth, eleventh, twelfth, and thirteenth aspects, the disease is pemphigus vulgaris (PV) or pemphigus foliaceus (PF).

Embodiment g 131 In a third embodiment (embodiment 13) of the tenth, eleventh, twelfth, and thirteenth s, and embodiments (10), (11), and (12) contained therein, the (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomer of 2~[(3R)-3—[4-amino—3—(2-fluoro—4-phenoxy— phenyl)pyrazolo[3,4—d]pyrimidin—1—yl]piperidine—1-carbonyl]~4—methyl—4—[4-(oxetan—3- yl)piperaziny1]pent-2—enenitrile; or a pharmaceutically acceptable salt of any of the foregoing nds is administered as a monotherapy.

Embodiment (14) In a fourth embodiment (embodiment 14) of the tenth, eleventh, twelfth, and thirteenth aspects, and embodiments (10), (11), and (12) contained therein, the (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomer of 2-[(3R)[4-amino-3—(2—fluoro-4—phenoxy— phenyl)pyrazolo[3,4-d]pyrimidin-1 ~y1]piperidine-l-carbonyl]methyl[4-(oxetan yl)piperazin~1~yl]pent—2—enenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds is administered in acute PV or acute PF in place of or in combination with terods and optionally in combination with an immunosuppressive agent chosen from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate l, methotrexate, dapsone, sulfasalazine, azathioprine, an anti—CD20 agent (such as rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar version thereof), anti— ha agent (such as entanercept, infliximab, golilumab, adalimumab, or certolizumab pegol or a biosimilar version thereof), anti—1L6 agent toward ligand or its ors (such as tocilizumab, mab, olokizumab, elsililumab, or siltuximab), anti—IL17 agent to ligand or its receptors (such as secukinumab, ustekinumab, brodalumab, or ixekizumab), anti-1L1 agent to ligand or its receptors (such as with rilonacept, canakinumab, or anakinra), anti-IL2 agent to ligand or its receptors (such as basiliximab or daclizumab), anti—CD2 agent such as alefacept, anti—CD3 agent such as muromonab—cd3, anti—CD80/86 agent such as abatacept or belatacept, anti-sphingosine—l-phosphate receptor agent such as fingolimod, 5 agent such as eculizumab, anti-integrin alpha4 agent such as natalizumab, anti- (x4137 agent such as vedolizumab, anti—mTOR agent such as mus or imus, anti—calcineurin agent such as tacrolimus, or anti-BAFF/BlyS agent (such as belimumab, VAY736, or blisibimod), omide and teriflunomide. _Preferably, the immunosuppressive agent is rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar version f.

Embodiment (15) In a fifteenth embodiment (embodiment 15) of the tenth, eleventh, twelfth, and enth s, and embodiments (10), (11), and (12) contained therein, the (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomer of 2—[(3R)—3—[4—amino—3—(2—fluoro—4—phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin—l —yl]piperidine—1—carbonyl]~4—methyl—4—[4—(oxetan yl)piperazin—l—yl]pent—2—enenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds is administered in acute pemphigus vulgaris or acute gus foliaceus in place of corticosteroids and administered optionally in combinations with an suppressive agent chosen from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, rexate, dapsone, sulfasalazine, azathioprine, an anti-CD20 agent (such as rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar version thereof), anti-TNFalpha agent (such as entanercept, imab, golilumab, adalimumab, or certolizumab pegol or a biosimilar n thereof), anti-1L6 agent toward ligand or its receptors (such as zumab, sarilumab, olokizumab, elsililumab, or siltuximab), Ll7 agent to ligand or its ors (such as secukinumab, ustekinumab, brodalumab, or ixekizumab), anti—1L1 agent to ligand or its receptors (such as with rilonacept, canakinumab, or anakinra), anti-1L2 agent to ligand or its receptors (such as ximab or daclizumab), anti-CD2 agent such as alefacept, anti-CD3 agent such as muromonab-cd3, anti—CD80/86 agent such as abatacept or belatacept, anti—sphingosine—l- phosphate receptor agent such as fingolimod, anti—C5 agent such as eculizumab, anti-integrin alpha4 agent such as natalizumab, anti— (1487 agent such as vedolizumab, anti—mTOR agent such as mus or everolimus, anti—calcineurin agent such as tacrolimus, or anti~ BAFF/BlyS agent (such as belimumab, VAY736, or imod), leflunomide and teriflunomide. Preferably, the immunosuppressive agent is rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar version thereof.

In yet another embodiment of any of the above aspects, the compound disclosed herein is injected locally into the patient to treat the condition of small areas of the body.

Examples of conditions for which local ions can be used include inflammation of a bursa tis of the hip, knee, elbow, or shoulder), a tendon (tendinitis, such as tennis elbow), and a joint (arthritis). Knee osteoarthritis, hip bursitis, painful foot conditions such as plantar fasciitis, and rotator cuff tendinitis may be treated by local injection of a compound of present disclosure. In a fourteenth aspect, ed is a method of treating an autoimmune disease and/or inflammatory disease in a mammal which method comprises administering to the mammal in need thereof a therapeutically effective amount of (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomer of 2-[(3R)-3—[4-amin0—3-(2~fluoro—4—phenoxy— phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine—1—carbonyl]-4—methyl—4-[4-(oxetan—3-I yl)piperazin-l-yl]pentenenitrile; or a pharmaceutically acceptable salt in combination with an suppressive agent having slow manifestions of clinical effect.

In one embodiment of the fourteenth aspect, the immunosuppressive agent is a biologic chosen from as interferon alpha, interferon gamma, an anti-CD20 agent (such as rituximab, umab, obinutuzumab, veltuzumab, or a biosimilar version thereof), anti— TNFalpha agent (such as entanercept, imab, golilumab, adalimumab, certolizumab pegol or a biosimilar version thereof), anti—1L6 agent toward ligand or its receptors (such as zumab, sarilumab, olokizumab, elsililumab, or siltuximab), anti-ILl7 agent to ligand or its ors (such as secukinumab, ustekinumab, brodalumab, or ixekizumab), anti~ILl agent to ligand or its receptors (such as with rilonacept, canakinumab, or anakinra), L2 agent to ligand or its receptors such as with ximab or daclizumab, anti—CD2 agent such as ept, anti—CD3 agent such as muromonab—cd3, anti—CD80/86 agent such as with abatacept orbelatacept, anti-C5 agent such as eculizumab, anti-integrin alpha4 agent such as natalizumab, anti- (14137 agent such as zumab, and anti—BAFF/BlyS agent (such as belimumab, VAY736, or blisibimod). Preferably, the immunosuppressive agent is rituximab, umab, obinutuzumab, or veltuzumab, or a biosimilar version thereof.

Representative advantages of the above s, include sparing the patient of disease activity without immunosuppression for prolonged periods that can lead to serious side effects. Additionally, the longer the acute flares and acute phases persist the more likely the disease process will progress and cause serious complications. Thus prompt remission of acute phases and acute flares will have a beneficial effect on the course of the disease, even without continued administration or maintenance of the active .

Embodiment ( 16) In any of the tenth, eleventh, twelfth, thirteenth and enth apects, embodiment (10), (11), (12), (13), (14) and (15), and embodiments contained therein the mammal is administered a therapeutically effective amouht of a substantially pure (E) or (Z) isomer of 2- [(3R)[4-amino-3~(2~fluoro~4~phenoxy—phenyl)pyrazolo[3,4~d]pyrimidin~1~yl]piperidine—l — carbonyl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile; or a ceutically acceptable salt thereof. Within embodiment (16), in a first embodiment, at least about 85% w/w of 2—[(3R)—3—[4-amino(2-fluorophenoxy—phenyl)pyrazolo[3,4-d]pyrimidin yl]piperidine—l —carbonyl]-4—methyl—4-[4-(oxetanyl)piperazinyl]pent-2—enenitrile; or at least about 85% wiw of a pharmaceutically able salt thereof is the (E) isomer. Within ment (16), in a second embodiment, at least about 90% w/w of 2-[(3R)—3-[4—amino—3— (2—fluoro—4—phenoxy—phenyl)pyrazolo [3 ,4-d]pyrimidin-1 -yl]piperidine— l —carb0nyl] methyl— 4—[4-(oxetanyl)piperazin—1—yl]pent—2-enenitrile; or at least about 90% w/w of a pharmaceutically acceptable salt thereof is the (E) isomer. Within embodiment (16), in a third embodiment, at least about 95% w/w of 2—[(3R)—3—[4-amino—3—(2-fluorophenoxy- phenyl)pyrazolo[3,4—d]pyrimidinyl]piperidine—l —carbonyl]—4—methyl[4-(oxetan-3— yl)piperazin—l-yl]pent-2—enenitrile; or at least about 95% w/w of a pharmaceutically acceptable salt thereof is the (E) isomer. Within embodiment ( 16), in a fourth ment, at least about 85% w/w of 2-[(3R)[4-amino(2-fluoro-4—phenoxy-phenyl)pyrazolo[3,4- d]pyrimidinyl]piperidine—1—carbonyl]—4-methyl—4—[4—(oxetan—3-yl)piperazin-l-yl]pent—2— enenitrile; or at least about 85% w/w of a pharmaceutically acceptable salt thereof is the (Z) isomer. Within embodiment (16), in a fifth embodiment, at least about 90% w/w of 2-[(3R)— mino—3-(2-fluoro-4—phenoxy-phenyl)pyrazolo[3,4—d]pyrimidin— 1-yl]piperidine carbonyl]~4~methyl~4~[4—(oxetanyl)piperazin~1~yl]pent—2—enenitrile; or at least about 90% w/w of a ceutically acceptable salt thereof is the (Z) isomer. Within ment (16), in a sixth embodiment, at least about 95% w/w of )~3-[4~amino—3—(2—fluoro~4— phenoxy-phenyl)pyrazolo[3,4—d]pyrimidinyl]piperidinecarbonyl]methyl—4-[4- (oxetan—3—y1)piperazin—1-yl]pent-2—enenitrile; or at least about 95% w/w of a pharmaceutically acceptable salt thereof is the (Z) isomer.

Within embodiment (16), and embodiments one to six contained therein, in one embodiment 2—[(3R)—3—[4—amino—3—(2—fluoro-4—phenoxy—phenyl)pyrazolo[3,4-d]pyrimidin—1— yl]piperidine—1~carbonyl]—4—methy1—4-[4—(oxetan—3-yl)piperazin-1—yl]pent-2—enenitrile is present as a free base or as a sulfonic (such as mesylate) or carboxylic acid salt. Within embodiment (16), and embodiments one to sixth contained therein, in another embodiment 2— [(3R)~3—[4—amino—3—(2—fluoro—4—phenoxy-phenyl)pyrazolo[3,4—d]pyrimidin— 1 ~yl]piperidine— 1 - carbonyl]-4—methyl—4—[4-(oxetan-3—yl)piperazin—1-yl]pent-2—enenitrile or a ic (such as mesylate) or carboxylic acid salt thereof is in amorphous form.

The present disclosure also included Embodiments 20—55 below: . A sulfonic acid or carboxylic acid salt of compound (1): N\ \ I N N N O 0 NoflkN/QN~<>O 2O (I) 21. The sulfonic acid or carboxylic acid salt of compound (I) of embodiment 20 wherein the salt is a sulfonic acid salt. 22. The sulfonic acid salt of compound (I) of embodiment 21 wherein the sulfonic acid salt is mono— or di-methanesulfonic acid, mono or di—benezenesulfonic acid, mono- or di-toluenesulfonic acid, or ethane-1,2-disulfonic acid salt. 23. The ic acid salt of compound (I) of embodiment 22 wherein the sulfonic salt is mono— or di—methanesulfonic acid salt. _23- 2015/016963 24. The sulfonic acid or carboxylic acid salt of compound (I) of embodiment 20 wherein the salt is a ylic acid salt.

. An amorphous form of a pharmaceutically acceptable salt of compound (I) tN/ N»: O o MoijNCN—Co 26. The amorphous form of a pharmaceutically acceptable salt of compound (I) of embodiment 25 wherein the pharmaceutically acceptbale salt is a sulfonic acid or a carboxylic acid salt. 27. The amorphous form of a pharmaceutically acceptable salt of nd (I) of embodiment 26 wherein the pharmaceutically acceptbale salt is a sulfonic acid salt. 28. The amorphous form of a pharmaceutically acceptable salt of compound (I) of embodiment 27 wherein the sulfonic acid salt is mono» or di-methanesulfonic acid, mono or di—benezenesulfonic acid, mono- or di-toluenesulfonic acid, or ethane—1,2-disulf0nic acid salt. 29. The amorphous form of a pharmaceutically acceptable salt of compound (I) of embodiment 27 wherein the sulfonic salt is mono— or di-methanesulfonic acid salt.

. The amorphous form of a pharmaceutically acceptable salt of compound (I) of embodiment 26 wherein the pharmaceutically acceptable salt is a ylic acid salt. 31. The amorphous form of a pharmaceutically acceptable salt of compound (I) of any of the ments 25—30 wherein the amorphous form is substantially free of any crystalline form(s) of the pharmaceutically able salt of compound (I). 32. The amorphous form of a pharmaceutically acceptable salt of compound (I) of any of the ments 25-30 wherein at least about 80% w/w of the pharmaceutically acceptable salt of compound (I) is in amorphous form. 33. The amorphous form of a pharmaceutically acceptable salt of nd (I) of any of the embodiments 25—30 wherein at least about 90% w/w of the pharmaceutically acceptable salt of compound (I) is in amorphous form. _24- 34. The ous form of a pharmaceutically acceptable salt of compound (I) of any of the embodiments 25—30 wherein at least about 99% w/w of the pharmaceutically acceptable salt of compound (I) is in amorphous form.

. The sulfonic acid or carboxylic acid salt of compound (I) of any of the embodiments 20—24 wherein the salt of nd (I) is a substantially pure E or Z isomer. 36. The amorphous form of a pharmaceutically acceptable salt of compound (I) of any of the embodiments 25—34 wherein the salt of nd (I) is a substantially pure E or Z 37. The sulfonic acid or carboxylic acid salt of compound (I) of embodiment 35 wherein at least about 80% w/w of the salt of compound (I) is the E isomer. 38. The sulfonic acid or carboxylic acid salt of compound (I) of embodiment 35 wherein at least about 90% w/w of the salt of compound (I) is the E isomer. 39. The sulfonic acid or ylic acid salt of compound (I) of embodiment 35 wherein at least about 95% w/w of the salt of compound (I) is the E isomer. 40. The sulfonic acid or carboxylic acid salt of compound (I) of embodiment 35 wherein at least about 80% w/w of the salt of compound (I) is the Z isomer. 4]. The sulfonic acid or carboxylic acid salt of compound (I) of embodiment 35 wherein at least about 90% w/w of the salt of compound (I) is the Z isomer. 42. The ic acid or carboxylic acid salt of compound (I) of embodiment 35 wherein at least about 95% w/w of the salt of compound (I) is the Z isomer. 43. The ous form of a pharmaceutically acceptable salt of nd (I) of embodiment 36 wherein at least about 80% w/w of the pharmaceutically acceptable salt of compound (I) is the E . 44. The amorphous form of a pharmaceutically acceptable salt of compound (I) of embodiment 36 wherein at least about 90% w/w of the pharmaceutically acceptable salt of compound (I) is the E . 45. The amorphous form of a pharmaceutically acceptable salt of compound (I) of embodiment 36 wherein at least about 95% w/w of the pharmaceutically acceptable salt of compound (I) is the E isomer. 46. The amorphous form of a pharmaceutically acceptable salt of compound (I) of embodiment 36 wherein at least about 80% w/w of the pharmaceutically acceptable salt of compound (I) is the Z isomer. 47. The amorphous form of a pharmaceutically acceptable salt of compound (I) of embodiment 36 wherein at least about 90% w/w of the pharmaceutically acceptable salt of compound (I) is the Z isomer. 48. The amorphous form of a pharmaceutically acceptable salt of compound (I) of embodiment 36 wherein at least about 95% w/w of the pharmaceutically acceptable salt of compound (I) is the Z isomer. 49. An amorphous form of mono- or dimesylate salt of compound (I) or a substantially pure (E) or (Z) isomer thereof having XRPD substantially as in Figure 4A and 4 respectively. 50. A pharmaceutical composition comprising the sulfonic acid or carboxylic acid salt of compound (I) of any of the embodiments 20—24, 35, and 37—42 or the amorphous form of a pharmaceutically able salt of compound (I) of any of the embodiments 25-34, 36, and 43—48. 51. A method of treating a autoimmune disease, an inflammatory disease, or cancer in a mammal in need of such ent which method comprises administering to the mammal, a pharmaceutical composition of embodiment 50. 52. The method of embodiment 51 wherein the mammal is a human in need of such treatment. 53. The method of embodiment 51 or 52 wherein the autoimmune disease is lupus, phemphigus vulgaris, omatosis with giitis, or rheumatoid arthritis. 54. A method of treating lupus nephritis, autoimmune hemolytic anemia, granulomatosis with polyangiitis, or pemphigus vulgaris in a mammal, comprising stering to said mammal a pharmaceutical composition sing: an (E) , (Z) isomer, or a e of (E) and (Z) isomer of )—3-[4—amino— 3-(2—fluoro-4—phenoxy—phenyl)pyrazolo[3,4—d]pyrimidinyl]piperidine~l-carbonyl]-4— methyl~4—[4—(oxetan-3—yl)piperazin-l—yl]pentenenitrile; or a ceutically acceptable salt of any of the foregoing compounds. 55. The method embodiment 54 wherein the pharmaceutical composition comprises a substantially pure (E) or (Z) isomer of 2—[(3R)—3—[4—amino—3—(2—fluoro—4—phenoxy- phenyl)pyrazolo[3,4—d]pyrimidin-1—yl]piperidine—1—carbonyl]—4—methyl—4—[4—(oxetan-3— yl)piperazinyl]pent—2-enenitrile, or a pharmaceutically acceptable salt thereof and the mammal is a human. ~26- BRIEF PTION OF THE FIGURES A representative HPLC trace of compound (I) prepared according to Example 1 representing separation of the E and Z s of compound (I) prepared according to e 1 is shown in Fig 1A below A representative XRPD diffractogram of an amorphous form of compound (I) having an E/Z ratio of about 9/ 1, prepared according to Example 1, is shown in Figure IB below.

A representative XRPD diffractogram for hemi-H2804 salt of compound (I) having an E/Z ratio of about 9/1 prepared ing to e 2 is shown in Figure 2A below.

A representative XRPD diffractogram for H2804 salt from ethylacetate of compound (I) having an E/Z ratio of about 9/1 prepared according to e 2 is shown in Figure 2B below.

A representative XRPD diffractogram of an amorphous form of mono— HCl salt of compound (I) having an E/Z ratio of about 9/1 prepared according to Example 3 is shown in Figure 3 below.

A representative lHNMR spectrum of mono—HCl salt having an E/Z ratio of about 9/1 prepared in DMSO-d6 according to Example 3 is shown in Figure 3A.

A representative XRPD diffractogram for mono—methanesulfonic acid salt of compound (I) having an E/Z ratio of about 9/1 prepared in MTBE according to Example 4 is shown in Figure 4A. 2O A representative XRPD diffractogram for di-methanesulfonic salt of compound (I) having an E/Z ratio of about 9/1 prepared in MTBE according to Example 4 is shown in Figure 4.

A representative lHNMR spectrum of dimesylate salt of nd (I) having an E/Z ratio of about 9/1 prepared in cyclohexane in CDC13 according to Example 4 is shown in Figure 4B.

A representative lHNMR spectrum of ethanesulfonic salt of compound (I) having an E/Z ratio of about 9/1 in cyclohexane in CDC13 prepared according to Example 4 is shown in Figure 4C.

A representative XRPD diffractogram for oxalic acid salt of compound (I) having an E/Z ratio of about 9/1 prepared in isopropyl acetate according to Example 5 is shown in Figure 5.

A representative lH—NMR spectrum of potential (1:1) oxalic acid salt of compound (I) having an E/Z ratio of about 9/1 ed according to Example 5 is shown in Figure 5A below.

WO 27310 A entative XRPD diffractogram for citric acid salt of compound (I) having an E/Z ratio of about 9/1 prepared according to Example 6 is shown in Figure 6.

Results from dog pemphigus foliaceus study conducted as bed in Example 7 are shown in Figs 7 and 8 below.

Definitions: Unless otherwise stated, the ing terms used in the specification and claims are defined for the es of this Application and have the following meaning. All undefined technical and scientific terms used in this Application have the meaning as commonly taood by one of ordinary skill in the art to which this invention belongs.

”Amorphous form” denotes a solid which does not possess a distinguishable crystal lattice and the molecular arrangement of molecules lack a long range order characteristic of a crystal. In particular amorphous denotes a material that does not show a sharp Bragg diffraction peak.

“Compound (I)” as used herein means, unless stated otherwise, E , Z isomer, or a mixture of (E) and (Z) s of 2~[(3R)«3-[4—amino—3—(2—fluorophenoxy— pheny1)pyrazolo[3,4—d]pyrimidin-1—y1]piperidine-1—carbony1]—4-methyl—4—[4—(oxetan yl)piperazin—1—yl]pent—2—enenitrile having the structure: N N //\ / \ N N N—<>O, “Mammal” as used herein means domesticated animals (such as dogs, cats, and horses), and humans. In one embodiment, mammal is a human.

A "pharmaceutically acceptable salt" as used herein means an acid addition salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the compound of which the salt is made (hereafter, sometimess referred to as “parent compound”). Such salts include salts, formed with inorganic acids such as hydrochloric acid, romic acid, sulfuric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2—ethanedisulfonic acid, esulfonic acid, enesulfonic acid, and the like.

A "pharmaceutically acceptable carrier or excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical ition that is generally safe, and r biologically nor otherwise undesirable, and includes a carrier or an excipient that is able for mammalian pharmaceutical use.

"Treating" or "treatment" of a e includes: (1) preventing the disease, ie. causing the clinical symptoms of the e not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

A "therapeutically effective amount" means the amount of a compound of the present disclosure that, when administered to a mammal in need or recognized need of treatment for treating a disease, is ient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

“Antisolvent” is a solvent in which a compound of the disclosure is less e.

For all analytical data discussed in this application, it should be noted that specific values depend on many factors, e.g., specific instrument, sample preparation and dual operator. The data obtained by a particular analytical technique with different experiments are “substantially the same” when characteristic data obtained using the same analytical technique (but may be obtained under different ions or using different ments) vary within i 10%, i5% or i 1%. A person of ry skill in the art will recognize characteristic data for each particular analytical technique when presented with data obtained by the analysis. For example, characteristic of data of a XRPD are sharp peaks for crystalline solid and ous halo for an amorphous solid.

“Substantially free” as used herein refers to a compound (or salt thereof) such as compound (I) wherein at least about 70% by weight of the compound (or salt thereof) is present as the given solid state form. For example, the phrase “amorphous form of a salt of compound (I) substantially free of any crystalline form(s) thereof” refers to a solid state form of a salt of compound (I) wherein more than about 70% by weight of the salt of compound (I) is in ous form with the remaining present in a crystalline form. In one embodiment, such compositions contain at least about 80% by weight of a salt of compound (I) is in amorphous form. In another embodiment at least about 85% by weight of a salt of compound (I) is in amorphous form. In yet another ment, at least about 90% by weight of a salt of nd (I) is in amorphous form. In yet another ment, at least about 95% by weight of a salt of nd (I) is in amorphous form. In yet another embodiment, at least about 97% by weight or about 98% by weight of a salt of compound (I) is in amorphous form. In yet another embodiment, at least about 99% by weight of a salt of compound (I) is in amorphous form. “About” as used herein means + or — 5% deviation from the listed value.

For example, a composition containing about 70% by weight of a component may contain 66.5% to 73.5% by weight of the component.

The relative amounts of crystalline and/or amorphous forms in a solid mixture can be ined by well known in the art. For example, X-Ray diffraction provides a convenient and practical means for quantitative determination of the relative amounts of crystalline and/or amorphous forms in a solid mixture. X—Ray diffraction is adaptable to quantitative applications because the intensities of the diffraction peaks of a given compound in a mixture are proportional to the fraction of the corresponding powder in the mixture. Although all salts of compound (I) are amorphous, if any crystalline form of nd (I) (or a salt thereof) is t in a mixture, percent composition of crystalline compound (I) (or a salt thereof) in an unknown composition can be determined. Preferably, the measurements are made on solid powder of compound (I) (or a salt thereof). The X-Ray powder diffraction patterns of an n composition may be compared to known quantitative standards containing pure crystalline forms, if any, of compound (I) (or a salt thereof) to identify the percent ratio of a particular crystalline form. If amorphous form is the major fraction of the composition, the amount may be further compared to the total weight of the solid subject to is. This is done by ing the relative intensities of the peaks from the diffraction pattern of the unknown solid powder composition with a calibration curve derived from the X-Ray diffraction patterns of pure known samples. The curve can be calibrated based on the X~Ray powder ction pattern for the strongest peak from a pure sample of crystalline forms of compound (I) (or a salt thereof). The calibration curve may be created in a manner known to those of skill in the art. For example, five or more artificial mixtures of crystalline forms of compound (I) (or a salt thereof), at different amounts, may be prepared. In a non—limiting example, such mixtures may n, 2%, 5%, 7%, 8%, and 10% of nd (I) (or a salt thereof) for each crystalline form. Then, X-Ray diffraction patterns are obtained for each artificial mixture using standard X—Ray diffraction techniques. Slight variations in peak positions, if any, may be accounted for by ing the location of the peak to be measured.

The intensities of the selected characteristic peak(s) for each of the artificial mixtures are then plotted against the known weight percentages of the lline form. The resulting plot is a calibration curve that allows determination of the amount of the crystalline forms of nd (I) (or a salt thereof) in an unknown sample. For the unknown mixture of crystalline and amorphous forms of compound (I) (or a salt thereof), the intensities of the selected teristic peak(s) in the mixture, relative to an intensity of this peak in a calibration mixture, may be used to ine the percentage of the given lline form in the composition, with the remainder determined to be the amorphous material. The overall crystallinity may be determined as follows: % Crystallinity=(C/A+C-B) X 100, where C is area under crystalline peaks, A is area under amorphous halo, and B is background noise due to air ring, fluorescence, etc.

“Substantially pure” as used herein in connection with an geometric or polymorphic isomeric form refers to a compound (or salt f or an amorphous form of a salt thereof) such as compound (I) wherein more than 70% by weight of the compound (or a salt thereof or an amorphous form of a salt thereof) is present as the given isomeric form. For example, the phrase “the salt or amorphous form of the salt of compound (I) is a ntially pure (E) isomer of compound (1)” refers to the salt or amorphous form of the salt of compound (I)having at least about 70% by weight of the salt or amorphous form of the salt of compound (I) being in the (E) isomeric form, and the phrase “the salt or amorphous form of the salt of compound (I) is a substantially pure (Z) isomer of compound (1)” refers to the salt or amorphous form of the salt of nd (I) having at least about 70% by weight of the salt or amorphous form of the salt of compound (I) being in the (Z) isomeric form. In one embodiment, at least about 80% by weight of the salt or amorphous form of the salt of compound (I) is the (E) form or at least about 80% by weight of the salt or amorphous form of the salt of compound (I) is the (Z) form. In another embodiment at least about 85% by weight of the salt or amorphous form of the salt of compound (I) is in the (E) form or at least about 85% by weight of the salt or amorphous form of the salt of compound (I) is in the (Z) form. In yet another embodiment, at least about 90% by weight of the salt or amorphous form of the salt of the nd (I) is in the (E) form or at least about 90% by weight of the salt or amorphous form of the salt of the compound (I) is in the (Z) form. In yet another embodiment, at least about 95% by weight of the salt or amorphous form of the salt of nd (I) is in the (E) form or at least about 95% by weight of the salt or amorphous form of the salt of compound (I) is in the (Z) form. In yet another embodiment, at least about 97% by weight, or about 98% by weight of the salt or amorphous form of the salt of nd (I) is in the (E) form or at least about 97% by weight, or about 98% by weight of the salt or amorphous form of the salt of compound (I) is in the (Z) form. In yet another embodiment, at least about 99% by weight of the salt or amorphous form of the salt of compound (I) is in the (E) form or at least about 99% by weight of the salt or amorphous form of the salt of compound (I) is in the (Z) form. Similar analysis would apply when Compound (I) is present in as ntially pure E or Z isomer. “About” as used herein means + or — 5% deviation from the listed value. For example, a composition ning about 70% by weight of a component may n 66.5% to 73.5% by weight of the component. The relative amounts of (E) and (Z) isomers in a solid mixture can be determined by well known in the art. One such method if disclosed herein below.

“Acute” as used herein means a disease with a rapid onset and/or a short course.

Treatment decisions often follow formal or informal algorithmic guidelines.

Treatment options can often be ranked or prioritized into lines of y: first-line therapy, second-line therapy, line therapy, and so on. First—line therapy is the first therapy that will be tried. Its priority over other options is usually either (1) formally ended on the basis of clinical trial evidence for its best-available combination of efficacy, safety, and/or tolerability or (2) chosen based on the clinical experience of the ian. If a first-line therapy either fails to resolve the issue or produces intolerable side effects, additional (second-line) therapies may be substituted or added to the treatment regimen, followed by third-line therapies, and so on. Accordingly, “first-line” therapy as used herein means therapy usually given when someone is diagnosed with a particular disease or condition and can be categorized as standard of care.

“Maintenance therapy” as used herein means a therapy, eutic regimen, or course of therapy which is administered subsequent to an l course of therapy administered to a patient with a disease. Maintenance therapy can be used to halt, slow down, or even e the progression of the disease, to maintain the improvement in health achieved by the initial treatment and/or enhance the gains achieved by the initial therapy.

“Flares” as used herein means an exacerbation of a chronic disease. Sometimes ed to as a flare—up, a flare occurs when ms of a disease that has been present for a time suddenly worsen. For example, in many arthritis ions the joints can flare with worsening of stiffness, pain, and swelling.

It will be understood by a person of ordinary skill in the art that when a compound is denoted as (R) stereoisomer (e.g., compound (1)), it may contain the corresponding (S) stereoiomer as an impurity i.e., the (S) stereoisomer may be present inless than about 5%, preferably less than 2% by wt.

Administration and Pharmaceutical ition In general, the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. eutically effective s of the compounds disclosed herein may range from about 0.01 to about 500 mg per kg mammal body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range, the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. Within this range, the dosage can be from about 200 mg to about 350 mg/bid or from 500 mg to 650 mg qd, For oral administration, the itions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount administered of the compound of this disclosure, i.e., compound (I), the sulfonic acid salt of compound (I), carboxylic acid salt of compound (I) or an amorphous form of a pharmaceutically acceptable salt of compound (I) and any embodiments thereof disclosed 2O above, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the mammal, the potency of the compound and/or pharmaceutically acceptable salt thereof being utilized, the route and form of administration, and other factors.

In general, compounds of this disclosure will be administered as pharmaceutical itions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), topically, or parenteral (e.g., intramuscular, intravenous or aneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, capsules, lids, powders, sustained release formulations, enteric coated or delayed release formulation, solutions, suspensions, elixirs, ls, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or es are red) and the bioavailability of the drug substance. Recently, pharmaceutical ations have been developed ally for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, US. Pat. No. 4,107,288 bes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. US. Pat. No. ,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a e modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that ts remarkably high bioavailability.

The compositions are comprised of, in general, a compound disclosed herein in combination with at least one ceutically acceptable excipient such as binders, surfactants, diluents, buffering agents, antiadherents, glidants, hydrophilic or hydrophobic rs, retardants, stabilizing agents or stabilizers, disintegrants or isintegrants, antioxidants, antifoaming agents, fillers, s, colors, lubricants, ts, preservatives, plasticizers,and sweeteners. Acceptable excipients are non—toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound disclosed herein. Such excipient may be any solid, liquid, semi—solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include , cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

The compounds of the present disclosure can also be administered intranasally.

Intranasal formulations are known in the art e.g., see US. Patent Nos. 4,476,116, 5,116,817 and 6,391,452, each of which is incorporated herein by reference. The choice of ents will depend upon the nature of the nasal dosage form e.g., solutions, suspensions, or powder.

For administration by inhalation, the compounds of the present disclosure may be in the form of solutions, suspensions, and powders. These formulations are administered as an aerosol, a mist, or a powder and can be delivered from rized packs or a zer with a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, nitrogen, carbon dioxide, etc. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. es and cartridges for use in an r may be formulated containing a powder mix of the compound disclosed herein and a le powder base such as lactose or starch.

Topical ation can be liquids, suspension, emulsions, and the like, and can be prepared by methods well known in the art. The formulation will n, on a weight percent (wt %) basis, from about 0.01—99.99 wt % of a compound and/0r pharmaceutically acceptable salt disclosed herein based on the total formulation, with the balance being one or more suitable pharmaceutical excipients amd can be administered in single or multiple doses.

Suitable excipients include polymers, surfactants, buffering or pH adjusting agents, tonicity and osmotic adjusting agent(s), preservatives, and dispersing agents.

Other suitable pharmaceutical excipients and their formulations are described in ton’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, ‘h ed., 2000).

The level of the compound in a ation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.0l-99.99 wt % of a compound disclosed herein based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.

The compounds of the present disclosure may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of the present disclosure or the other drugs may have utility, where the combination of the drugs er are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used ore, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present sure is red. However, the combination therapy may also include therapies in which the compound of the present disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present sure and the other active ients may be used in lower doses than when each is used singly.

Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other active ingredients, in on to a compound of the present disclosure.

WO 27310 The above combinations e combinations of a compound of the present disclosure not only with one other active compound, but also with two or more other active compounds. se, compounds of the present disclosure may be used in combination with other drugs that are used in the prevention, treatment, l, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present disclosure are useful.

Such other drugs may be administered, by a route and in an amount commonly used ore by those skilled in the art, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present disclosure is preferred. Accordingly, the pharmaceutical itions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a nd of the present disclosure. The weight ratio of the compound of the present disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ient. Generally, an effective dose of each will be used.

Where the mammal is suffering from or at risk of suffering from an autoimmune disease, an inflammatory disease, or an allergy disease, a compound of present disclosure can be used in with one or more of the following therapeutic agents in any combination: immunosuppressants (e.g., tacrolimus, iethylstilb, rapamicin, rexate, cyclophosphamide, azathioprine, mercaptopurine, enolate, or FTY720), glucocorticoids (e.g., prednisone, cortisone e, prednisolone, methylprednisolone, dexamethasone, betamethasone, inolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti—inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2~arylpropionic acids, N~arylanthranilic acids, oxicams, coxibs, or sulphonanilides), Cox—2—specific inhibitors (e.g., valdecoxib, celecoxib, or xib), leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, TNF—.alpha. binding proteins (e.g., infliximab, etanercept, or umab), abatacept, anakinra, interferon—beta, interferon—.gamma, interleukin-2, allergy vaccines, antihistamines, ukotrienes, beta—agonists, theophylline, and anticholinergics.

Where the mammal is suffering from or at risk of ing from a B-cell proliferative disorder (e.g., plasma cell myeloma), the mammalcan be treated with a compound disclosed herein in any combination with one or more other anti-cancer agents. In some embodiments, one or more of the anti-cancer agents are proapoptotic agents. Examples of anti—cancer agents include, but are not d to, any of the following: gossyphol, genasense, polyphenol E, fusin, all trans—retinoic acid (ATRA), bryostatin, tumor necrosis —related apoptosis-inducing ligand (TRAIL), 5—aza—2’—deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, ide, gemcitabine, imatinib (GleevecTM), geldanamycin, 17-N- Allylamino—17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11—7082, , or PD184352, TaxolTM, also referred to as “paclitaxel”, which is a well-known anti~cancer drug which acts by enhancing and stabilizing microtubule ion, and docetaxol, such as TaxotereTM. Compounds that have the basic taxane skeleton as a common structure e, have also been shown to have the ability to arrest cells in the G2—M phases due to stabilized ubules and may be useful for ng cancer in combination with the compounds described herein.

Further examples of anti-cancer agents for use in combination with a compound disclosed herein include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY—l42886, SB239063, 25, BAY 6, wortmannin, or 02; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).

Other anti—cancer agents that can be employed in combination with a compound disclosed herein include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; a; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; ide dimesylate; bizelesin; bleomycin e; brequinar sodium; bropirimine; an; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; ifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; atin; enpromate; epipropidine; epirubicin hydrochloride; zole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; abine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rILZ), interferon alfa-2a; interferon alfa-2b; eron alfa-nl; interferon alfa—n3; interferon beta-la; interferon gamma-l b; atin; irinotecan hydrochloride; lanreotide acetate; ole; leuprolide acetate; ole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; ocol; maytansine; mechlorethamine hydrochloride; rol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate ; ine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; ycin; pentamustine; peplomycin e; perfosfamide; oman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; mustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; furin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; onigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine ate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine e; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

Other anti—cancer agents that can be employed in combination with a nd and/or pharmaceutically acceptable salt disclosed herein include: 20-epi—1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti— dorsalizing morphogenetic protein—1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara—CDP—DL—PTBA; arginine deaminase; asulacrine; tane; atrimustine; tatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; in III derivatives; balanol; batimastat; L antagonists; hlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; imine; budotitane; buthionine sulfoximine; WO 27310 calcipotriol; calphostin C; camptothecin derivatives; canarypox IL—2; capecitabine; carboxamide-amino—triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived tor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; rphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; mycin B; tastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; phycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro—S-azacytidine; amycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; ustine analogue; estrogen ts; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; ole; bine; fenretinide; filgrastim; fmasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hloride; imex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; m nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; uane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; ole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+pr0gesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic um compounds; lissoclinamide 7; lobaplatin; cine; lometrexol; lonidamine; losoxantrone; lovastatin; bine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase tors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; cin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; onal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+iethylstilbe cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor l-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N—acetyldinaline; N- substituted benzamides; lin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; atin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; onic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate ; tatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; nil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; um complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; 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 orylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie ate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; mes; R11 retinamide; imide; rohitukine; romurtide; roquinimex; rubiginone B1; l; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived 1; sense oligonucleotides; signal transduction inhibitors; signal uction tors; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; medin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; pentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan ; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; omine; lastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; rexate; triptorelin; tropisetron; eride; ne kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital derived growth inhibitory factor; ase receptor antagonists; vapreotide; in B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Yet other anticancer agents that can be employed in combination with a compound sed herein include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or nes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

Examples of natural products useful in combination with a compound disclosed herein include but are not limited to vinca alkaloids (e.g., - 41 —iethylstil, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, cin), enzymes (e,g., L—asparaginase), or biological response modifiers (e.g., interferon alpha).

Examples of ting agents that can be employed in combination a compound disclosed herein include, but are not d to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., thlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), oureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or nes (decarbazine, etc.) Examples of antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e. g., fluorouracil, floxuridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of hormones and antagonists useful in combination with a compound disclosed herein include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol e, yprogesterone e), estrogens (e.g., - 41 —iethylstilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone nate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., ntrone), substituted urea (e.g., hydroxyurea), methyl hydrazine WO 27310 derivative (e. g., procarbazine), adrenocortical suppressant (e. g., mitotane, lutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2~M phases due to stabilized microtubules and which can be used in combination with a compound of the present disclosure e without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R—55104), atin 10 (also known as DLS—lO and NSC—376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC—639829, Discodermolide (also known as NVP—XX—A—296), 1 (Abbott, also known as E—7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and statin 9), Cemadotin hydrochloride (also known as 793 and NSC—D—669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS—862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N—oxide, lone A N—oxide, 16—aza—epothilone B, 21—aminoepothilone B (also known as BMS- 310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26— fluoroepothilone), Auristatin PE (also known as 4663), Soblidotin (also known as TZT-1027), LS—4559-P (Pharmacia, also known as LS—4577), LS-4578 (Pharmacia, also known as LSP), LS—4477 (Pharmacia), LS~4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ—3358 (Daiichi), FR~182877 (Fujisawa, also known as WS—9885B), GS-164 (Takeda), GS—198 (Takeda), KAR-2 (Hungarian Academy of Sciences), ESP-223651 (BASF, also known as 1 and LU—223651), SAH—49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM—97 (Armad/Kyowa Hakko), AM—132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN—5005 (Indena), Cryptophycin 52 (also known as LY—355703), AC-7739 (Ajinomoto, also known as 63A and CS-39.HC1), AC—7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS—39—L—Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, nsol, Centaureidin (also known as NSC-106969), T— 138067 ik, also known as T—67, TL-138067 and TI—138067), COBRA—1 (Parker Hughes Institute, also known as DDE-261 and WHI—261), H10 (Kansas State University), H16 (Kansas State sity), Oncocidin A1 (also known as 6 and DIME), DDE- 313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA~2 r Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3—IAABU (Cytoskeleton/Mt.

Sinai School of Medicine, also known as MF~569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A—105972 (Abbott), Hemiasterlin, 3—BAABU 2015/016963 keleton/Mt. Sinai School of Medicine, also known as ), TMPN (Arizona State University), Vanadocene acetylacetonate, T—138026 (Tularik), Monsatrol, Inanocine (also known as NSC—698666), 3—1AABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204l97 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR—115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z— Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D—64131 (Asta ), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI—2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A—259754 (Abbott), Diozostatin, (—)-Phenylahistin (also known as NSCL—96F037), D—68838 (Asta Medica), 6 (Asta Medica), Myoseverin B, D—43411 (Zentaris, also known as D—81862), A—289099 t), A-3l8315 (Abbott), HTI—286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D—82317 (Zentaris), 8 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, -007 (National Health Research utes), and SSR—250411 (Sanofi).

Where the mammal is suffering from or at risk of suffering from a thromboembolic disorder (e.g., stroke), the mammal can be treated with a compound disclosed herein in any ation with one or more other anti—thromboembolic agents. Examples of anti» thromboembolic agents include, but are not limited to, any of the following: thrombolytic agents (e.g., alteplase anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX—9065a, otamixaban, LY517717, or YM150), ticlopidine, clopidogrel, CS—747 (prasugrel, LY640315), ximelagatran, or BIBR 1048.

Experimentals Methods of Analysis 1H—NMR experiments were performed on a Bruker AV400 (1H frequency: 400 MHZ). lH—NMR experiments of each sample were performed in DMSO—d6 or CDC13 and each sample was prepared to ca. 5mg/mL concentration.

Ion tography was conducted on Dioned ICS—3000 ion tograph equipmed with Dionex Ionpac ASl 1~HC, 4 x 250 mm column with AGl l—HC colum guard at 1.5 ml/min at 30 0C. The eluent was 5 mM NaOH. Ions were detected using a conductivity detector.

The XRPD analysis was carried out on a Siemens D5000 diffractometer, scanning the samples n 3 and 30 O2—theta en 3 and 50 °2—theta when analysing input materials) with Cu K-alpha radiation source. The material was gently compressed onto a glass disc inserted into an XRPD sample . The samples were then loaded into the diffractometer running in reflection mode and analysed.

High Performance Liquid Chromatograophy (HPLC) was conducted on t 1100 equipped with a column heater, gradient elution capability, an autosampler and a UV detector. The column was Zorbax SB—Phenyl at 40 °C and a eluent was water/methanol gradient with 0.1% methane sulfonic acid and UV ion at 225nm. Total run time was 8 minutes. The following gradient was used (A is water, and B is methanol): s %A %B 0.0 40 60 .0 20 80 7.0 20 80 7.25 40 60 8.0 40 60 Example 1 Synthesis of 2—[(3R)-3—[4—amino—3—(2—fluoro—4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin—1— yl]~piperidine~1~carbonyl]~4—methyl—4-[4-(oxetanyl)piperazin—1-yl]pent~2—enenitrile N N o 0 NZ}NCN{>0 To a on of 3-[(3R)—3—[4-amino—3-(2—flu0r0-4—phenoxy—phenyl)pyrazolo[3,4- d]pyrimidin-1—yl]—1-piperidyl]oxo—propanenitrile (15 g, ol), 2-methy1—2—[4— (oxetan—3—yl)piperazin-l-yl]propanal (794.25mg, 3.74mmol) in DCM (40mL), pyrrolidine (1.54mL,18.71mmol) at 0-5 °C was added, which is followed by TMS—Cl (1.58mL, 12.47mmol). The reaction mixture was stirred at 0—5 °C for 3 h and was quenched with 1 M potassium phosphate buffer (pH 3). Layers were separated and the organic layer was washed once more with 1 M potassium phosphate buffer (pH 3). The organic layer was extracted WO 27310 withl M potassium Phosphate buffer at pH 1.5. Layers were ted. The aqueous phase contained the desired product while the impurities stayed in the organic phase. The aqueous phase was neutralized with l M ium phosphate (pH 7) and was extracted with isopropylacetate (10 volumes). Upon concentration 2-[(3R)[4-amino(2—fluoro-4~ phenoxy—pheny1)pyrazolo[3,4—d]pyrimidin-1—yl]piperidine—l-carbonyl]—4-methyl-4—[4— n—3-yl)piperazin—1—yl]pent—2—enenitrile was obtained as a foam having >99% HPLC purity. MS (pos. ion) m/z: 666 (M+1).

The foam containing high levels of residual solvent was dissolved in 2 M HCl and the resulting solution was placed under vacuum to remove residual organic solvents. pH of the solution was then ed to ~ 7 and the resulting paste was ed and dried in vacuum without heat. This resulted in isolation of 2-[(3R)-3—[4—amino—3—(2—fluoro—4—phenoxy— phenyl)pyrazolo[3 ,4—d]pyrimidin—1-yl]piperidine~1~carb0nyl]~4—methyl«4—[4—(oxetan~3- erazin—1—y1]pentenenitrile containing residual water up to 10%. Drying under vacuum without heat s the water level but lead to generation of impurities.

Step 1A Alternatively, the pylacetate solution of 2—[(3R)—3—[4—amino—3—(2-fluoro—4— phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l -yl]piperidine-1—carbonyl]~4-methyl-4~[4~ (oxetan—3-yl)piperazin—l —yl]pent-2—enenitrile can be concentrated to 4 vol and added to heptane (20 volume) at 0 °C. The resulting suspension was stirred at 0 °C overnight and the product was filtered, washed twice with heptane and dried at 45 °C for 2 days under vacuum to give 2-[(3R)—3—[4-amino—3-(2—fluoro-4—phenoxy—phenyl)pyrazolo[3,4—d]pyrimidin-l— yl]piperidine—1—carbony1]—4-methyl—4—[4-(0xetan-3—yl)piperazinyl]pent—2—enenitrile in 85 — 9O % yield as a free flowing solid. However, the solids obtained by this method contained high residual solvents (3.9 wt% isopropylacetate and 1.7 wt% heptane). In addition, the free base form was not very stable as degradation products were observed during the drying process at less than 45 °C.

Salt formation Example 2 Preparation of 2-[(3R)[4-amino—3—(2—fluoro—4—phen0xy-phenyl)—pyrazolo[3,4—d]pyrimidin— 1-yl]—piperidine—1—carb0ny1]~4—methyl-4—[4—(0xetan-3—y1)-piperazin—1—y1]pent—2—enenitrile hemisulfate and sulfate salt Hemisulfate: WO 27310 To the solution of 2—[(3R)~3~[4~amino(2—fluoro-4—phenoxy—phenyl)-pyrazolo[3,4- d]pyrimidin-1—yl]-piperidine—1—carbonyl]-4—methyl—4—[4-(oxetan—3—yl)-piperazinyl]pent enenitrile (4.2 g) in EtOAc (60 mL, 15 vol) was added sulfuric acid (0.31 g, 0.17 mL, 0.5 eq) in EtOAc (20 mL, 5 vol) at ambient temperature. The suspension was stirred at ambient temperature for ~ 2 hr and then 40 °C for 4 hr and then at ambient temperature for at least 1 hr. After filtration and drying at ambient ature under vacuum, 1.5 g of white powder was obtained. Solubility of the hemi—sulfate at ambient temperature was > 100 mg/mL in water.

Sulfate salt To the solution of )—3—[4-amino(2—fluorophenoxy—phenyl)-pyrazolo[3,4— d]pyrimidin- l -yl] —piperidine- l -carbonyl] ~4—methyl—4-[4-(oxetan-3—yl)-piperazin— 1 —yl]pent-2— enenitrile (810 mg) in EtOAc (8 mL, 10 vol) was added sulfuric acid (0.06 mL, 1.0 equiv.) in EtOAc (2.5 mL, 5 vol) at ambient temperature. The resulting suspension was stirred at 40 °C for 2 hr and then cooled to ambient temperature for at least 1 hr. After filtration, solids were dried by suction under Argon for 1 h to give a white powder (0.68 g) in 69% yield.

Salt form Amorphous Consistent withstructur Amorphous Consistent with structure Example 3 Preparation of 2-[(3R)—3-[4—amino(2-fluoro-4—phenoxy—phenyl)-pyrazolo[3,4- midinyl]—piperidinecarbony1]~4—methyl[4-(oxetan—3-yl)—piperazin—1—y1]pent enenitrile hloride To a on of 2—[(3R)—3—{4—amino—3-(2—fluoro—4—phenoxy—phenyl)pyrazolo[3,4— d]pyrimidin—l—yl]piperidinecarbonyl]methy1—4-[4—(oxetan-3~yl)piperazin—1—yl]pent enenitrile (100 mg, 0.15 mmol) in CH2C12 (lml) at ambient temperature was added 2 -46— equivalent of HCl (0.3 mmol, 0.15 ml of 2M HCl in 1:1 dioaxane:CH2C12). The resulting homogeneous solution was stirred at ambient ature for 1 h and was added dropwise to volumes of ethylacetate (as compared to CH2C12) resulting in formation of a white solid.

The mixtures was aged at t ature for 1h and placed at 2-8 C for 19 h. Upon filtration and washing of the filter cake with cetate and drying a white solid was obtained. Analysis by XRPD indicated formation of an amorphous solid. Both 1H—NMR and IC analysis indicated formation of the salt. IC indicated formation mono—HCI salt.

Solvent Antisolvent Amorphous Consistent 811' Example 4 General procedure for preparation of 2-[(3R)—3—[4-amino—3-(2—fluoro—4-phenoxy— pheny1)pyrazolo[3,4—d]pyrimidin—1—y1]—piperidine—1—carbonyl]-4—methyl—4-[4-(oxetanyl)- piperazin-l-yl]pent—2—enenitrile mono- and di—mesylate salts To a on of 2—[(3R)—3—[4—amino—3-(2—fluorophenoxy—phenyl)pyrazolo[3,4— d]pyrimidinyl]piperidinecarbonyl]methyl—4—[4-(oxetan—3—yl)piperazin-1—yl]pent—2- enenitrile (100 mg, 0.15 mmol) in CH2C12 (1 ml) at ambient temperature was added either 1 equivalent of methanesulfonic acid (0.15 mmol, 0.2 ml of 74 mg/ml solution in CH2C12) or 2 equivalent of methanesulfonic acid (0.3 mmol, 0.4 ml of 74 mg/ml solution in CHzClz). The resulting homogeneous solution was stirred at ambient temperature for 1 h and was added dropwise to 10 volumes of antisolvents (ethylacetate, methyl tert—butylether (MTBE), 0r cyclohexane) (10 ml as compared to CH2C12) resulting in formation of a white solid. The mixture was aged at ambient temperature for 1h and placed at 2—8 °C for 19 h. Upon tion and washing of the filter cake with the lvent and drying, a white solid was obtained. Analysis by XRPD indicated formation of an amorphous solid. Both 1H-NMR and IC analysis ted formation of the salt as well as counterion ratio.

Alternatively 2—[(3R)[4—amino—3-(2-fluor0—4-phenoxy-phenyl)pyrazol0[3,4-d]— pyrimidin- 1 —yl]piperidine- l -carbony1] methy1[4-(oxetany1)piperaziny1]pent enenitrile can be dissolved in 4 volumes of isopropylacetate and added to 2 equivalent of methanesulfonic acid in 6 volumes of isopropylacetate at 0 °C to generate the dimesylate salt.

Salt form Antisolvent IC— mesylate content] Amorphous Consistent with salt ous 12.5% Consistent with salt 2MSA CH2C12 MTBE Amorphous 22.8% Consistent with salt MSA CH2C12 MTBE Amorphous 14.8% tent with salt 2MSA CH2C12 Cyclohexane Amorphous 21.8% Consistent with 2:1 salt MSA CH2C12 Cyclohexane Amorphous 13.9% Consistent with 1:1 salt 2MSA IPAC ND tent with salt 1. Theoretical mesylate content, monomesylate=12.6% and dimesylate=22.4%, ND: not determined Example 5 General procedure for the preparation of carboxylate salt Approximately 20 mg of the compound (I) was dissolved in minimum amount of the allocated solvent system. These were then mixed with the appropriate number of lents of counterion dissolved or slurried in the allocated solvent.

If compound (I) was insoluble in the selected solvent, slurry of the sample was used after adding 300 pL.

If the acid was insoluble in the selected solvent, slurry of the acid was used after adding 300 [AL If the acid was a liquid, the acid was added to the dissolved/slurried compound (I) from a stock solution in the allocated solvent.

The suspensions/ precipitates resulting from the mixtures of compound (I) were temperature cycled between ambient (ca. 22°C) and 40°C in 4 hour cycles for ca. 48 hrs (the cooling/heating rate after each 4 hour period was ca. 1°C/min). The mixtures were visually checked and any solids present were isolated and d to dry at ambient conditions prior to is. Where no solid was present, samples were allowed to evaporate at ambient.

Samples which ed amorphous al, after the treatment ed above, were re— dissolved and itated using anti-solvent (tert—butylmethylether) addition methods at ambient conditions (ca. 22°C). Le. the selected anti—solvent was added to each solution, until no further precipitation could be observed visually or until no more anti—solvent could be added. The solvents used in this preparation were acetonitrile, acetone, isopropyl acetate, THF and MTBE. The acid used were oxalic acid, L-aspartic acid, maleic acid, c acid, L-tartaric acid, and fumaric acid.

Example 6 General procedure for ation of 2-[(3R)[4—amino(2-fluoro-4—phenoxy— phenyl)pyrazolo[3,4-d]pyrimidin—1-yl]-piperidinecarb0nyl]—4—methyl—4-[4—(0xetan—3-yl)— piperazin—l-yl]pent—2-enenitrile hemicitrate salt To a solution 2-[(3R)—3~[4-amino—3—(2-fluorophenoxy-phenyl)pyrazolo[3,4—d]— pyrimidin-l-yl]piperidine—1-Carbonyl]methyl{4-(oxetanyl)piperazinyl]pent enenitrile (5 g, 7.5 mmol) in l (50 ml) was added citric acid (720.5 mg, 3.76 mmol) dissolved in 2 m1 of water. Mixture was stirred at t temperature for 15 min, additional 0.5 ml of water was added and the mixture was stirred for 1 h, concentrated in vacuo to a 2015/016963 gum. Ethanol was added and the mixture was trated. This process was repeated twice more and then CH2C12 was added to the mixture. Upon concentration a white solid was obtained which was tumble dried under reduced pressure at 40 C for 4 h, then in a vacuum oven for 19h to give 5.4 g of a solid. Analysis by XRD indicated formation of an amorphous solid.

Example 7 Dog Pemphigus Foliaceus Study A 30 kg Doberman dog with a characteristic first presentation of pemphigus folliaceus on the nose and paws was administered an oral dose of 500 mg daily of the BTK inhibitor 2—(3—(4-amino-3—(2-fluoro—4-phenoxypheny])—1H-pyrazolo[3,4—d]-pyrimidin—l- yl)piperidine—l—carbonyl)-4,4—dimethylpentenenitrile instead of the usual treatment for pemphigus of high dose corticosteroids (typically 1-2 mg/kg). This dose resulted in a level of BTK occupancy 24 hours after each dose of imately 70% as confirmed by blood taken 24 hours after the first dose.

The dog responded clinically to the drug as a monotherapy within three days, with improved eating and ambulation noted by the owner. At the one week follow up visit both owner and observing veterinarian reported improved general health and commencement of pemphigus lesion healing. The ing veterinarian commented that the improvement was “just like with osteroids” and recommended that corticosteroid therapy did not need to be commenced. No well-known corticosteroid—like adverse effects in canines, such as polyuria, polydipsia, polyphagia or weight gain, were noted.

After two weeks of treatment, the l health of the dog was excellent and skin lesions continued to improve. By four weeks, skin lesions had completely healed (see Figures 1 and 2).

The surprising conclusion of this experiment is that adequate doses of a BTK inhibitor are effective and safe as the acute treatment for gus folliaceus in a dog, replacing the need for corticosteroid y.

As shown in Table 3, dog PF and human PV share many similar characteristics that make generalization of treatment effects for human disease from observations of the dog disease credible.

Table 3 Comparison of dog pemphigus foliaceus (PF) and human gus vulgaris (PV) Naturally occurring autoimmune blistering e tigens to mal proteins Never resolves spontaneously Mainstay of treatment high dose corticosteroids Early disease response to corticosteroids 1—2 weeks \/ Full disease control with corticosteroids takes 4—12 weeks Relapses without nance treatment High mortality in first year, partly presumed due to high dose corticosteroids In addition, the y of (R, E)—2-(3—(4—amino—3—(2—fluoro—4—phen0xyphenyl)—lH— pyrazolo[3,4-d]—pyrimidin—l—y1)piperidine-1—carbonyl)—4,4-dimethylpent—2-enenitrile to rapidly control dog PF suggests that adequate doses of a BTK inhibitor can replace corticosteroids not just in human PV but in other diseases where corticosteroids are used acutely.

Formulation Examples The following are representative pharmaceutical ations containing a compound disclosed herein.

Parenteral Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a compound disclosed herein is dissolved in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL. The mixture is incorporated into a dosage unit form suitable for administration by injection.

Oral Composition -51, To prepare a pharmaceutical composition for oral delivery, 400 mg of a compound disclosed herein and the following ingredients are mixed intimately and pressed into single scored tablets.

Tablet Formulation The ing ingredients are mixed intimately and d into single scored s.

Ingredient Quantity per tablet compound of this disclosure 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 Capsule Formulation The following ingredients are mixed intimately and loaded into a hard—shell gelatin capsule. ient Quantity per capsule compound of this disclosure 200 lactose spray dried 148 magnesium te 2 Inhalation Composition To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride on. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Topical Gel Composition To e a pharmaceutical topical gel composition, 100 mg of of a salt of a compound sed herein is mixed with 1.75 g of hydroxypropyl celluose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

Ophthalmic Solution Composition To e a pharmaceutical mic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and d using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

Nasal spray solution To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 pl of spray for each application.

Claims (29)

What is Claimed:

1. A method of treating pemphigus vulgaris in a non-human mammal, comprising administering to said non-human mammal a pharmaceutical composition comprising a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2- 3-[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]- 4-methyl[4-(oxetanyl)piperazinyl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds.

2. A method of treating pemphigus vulgaris or pemphigus foliaceus in a non-human mammal in need thereof where corticosteroid therapy is used as the first or second line therapy comprising stering to said non-human mammal in need of said ent a therapeutically effective amount of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) s of 2- [(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]-pyrimidinyl]piperidine carbonyl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile; or a pharmaceutically able salt of any of the foregoing compounds, in place of or in combination with said corticosteroid therapy; and optionally stering said (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluoro phenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetan yl)piperazinyl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds in combination with: a noncorticosteroidal immunosupressive agent, or an antiinflammatory agent, or both a noncorticosteroidal immunosupressive agent and an antiinflammatory agent.

3. A method of treating pemphigus vulgaris or pemphigus eus in a non-human mammal in need f where osteroid therapy is used as the first or second line maintenance therapy comprising administering to said non-human mammal in need of said treatment a therapeutically effective amount of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) s of 2- [(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]- 4-methyl[4-(oxetanyl)piperazinyl]pentenenitrile, or a pharmaceutically acceptable salt of any of the foregoing compounds, in place of or in combination with said corticosteroid therapy; and optionally administering said (E) isomer, (Z) isomer, or a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluoro phenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetan yl)piperazinyl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing nds in combination with: a noncorticosteroidal immunosupressive agent, or an antiinflammatory agent, or both a noncorticosteroidal immunosupressive agent and an antiinflammatory agent.

4. The method of any one of Claims 1-3, wherein the said nd is a substantially pure (E) or (Z) isomer of )[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidin yl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile, or a pharmaceutically acceptable salt of said compound.

5. The method of Claim 4, wherein at least about 85% w/w of 2-[(3R)[4-amino(2-fluoro phenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetan yl)piperazinyl]pentenenitrile or at least about 85% w/w of a pharmaceutically acceptable salt of 2-[(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidine carbonyl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile is the (E) isomer, preferably wherein at least about 90% w/w of 2-[(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4- d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile or at least about 90 % w/w of a pharmaceutically acceptable salt of 2-[(3R)[4-amino(2-fluoro phenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetan yl)piperazinyl]pentenenitrile is the (E) .

6. The method of any one of Claims 1-5 wherein the compound is 2-[(3R)[4-amino(2- fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4- nyl)piperazinyl]pentenenitrile.

7. Use of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidine carbonyl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing nds for the cture of a medicament for treating pemphigus vulgaris.

8. Use of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidine carbonyl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile; or a pharmaceutically acceptable salt of any of the foregoing nds for the manufacture of a medicament for treating pemphigus vulgaris or pemphigus foliaceus where corticosteroid therapy is used as the first or second line therapy, n said medicament is to be administered in place of or in combination with said corticosteroid therapy; and optionally wherein said medicament is to be administered in combination with: a noncorticosteroidal immunosupressive agent, or an antiinflammatory agent, or both a noncorticosteroidal immunosupressive agent and an antiinflammatory agent.

9. Use of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidine yl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile; or a ceutically acceptable salt of any of the ing compounds for the manufacture of a medicament for treating pemphigus vulgaris or pemphigus eus where corticosteroid therapy is used as the first or second line maintenance therapy, wherein said medicament is to be administered in place of or in combination with said corticosteroid therapy; and optionally wherein said medicament is to be administered in ation with: a noncorticosteroidal immunosupressive agent, or an antiinflammatory agent, or both a noncorticosteroidal immunosupressive agent and an antiinflammatory agent.

10. The use of any one of Claims 7-9, wherein the compound is a substantially pure (E) or (Z) isomer of 2-[(3R)[4-amino(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidine- 1-carbonyl]methyl[4-(oxetanyl)piperazinyl]pentenenitrile; or a pharmaceutically able salt of the compound.

11. The use of Claim 10, wherein at least 85% w/w of 2-[(3R)[4-amino(2-fluorophenoxyphenyl )pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazin yl]pentenenitrile or at least 85% w/w of a pharmaceutically acceptable salt of 2-[(3R)[4-amino- 3-(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4- nyl)piperazinyl]pentenenitrile is the (E) isomer.

12. The use of Claim 10 wherein, at least 90% w/w of 2-[(3R)[4-amino(2-fluorophenoxyphenyl )pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazin tenenitrile or at least 90% w/w of a pharmaceutically acceptable salt of 2-[(3R)[4-amino- 3-(2-fluorophenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4- (oxetanyl)piperazinyl]pentenenitrile is the (E) isomer.

13. The use of any one of Claims 9-12, n the compound is 2-[(3R)[4-amino(2-fluoro- 4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetan yl)piperazinyl]pentenenitrile.

14. A sulfonic acid or carboxylic acid salt of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluorophenoxyphenyl )pyrazolo[3,4-d]-pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazin yl]pentenenitrile, ably wherein the sulfonic salt or carboxylic acid salt is a mono- or dimethanesulfonic acid salt.

15. An amorphous form of a pharmaceutically acceptable salt of a compound selected from (E) isomer, (Z) isomer, and a mixture of (E) and (Z) isomers of 2-[(3R)[4-amino(2-fluorophenoxyphenyl )pyrazolo[3,4-d]-pyrimidinyl]piperidinecarbonyl]methyl[4-(oxetanyl)piperazin yl]pentenenitrile.

16. The amorphous form of the pharmaceutically acceptable salt of the compound of Claim 15, wherein the pharmaceutically acceptable salt is a sulfonic acid or a carboxylic acid salt, preferably wherein the pharmaceutically acceptable salt is a mono- or di-methanesulfonic acid salt.

17. The amorphous form of the pharmaceutically acceptable salt of the compound of claim 15 or 16, wherein the amorphous form is substantially free of any crystalline ) of the pharmaceutically acceptable salt of said compound.

18. The amorphous form of the pharmaceutically acceptable salt of the compound of any one of Claims 15-17, wherein at least about 90% w/w of the pharmaceutically acceptable salt of said compound is in amorphous form.

19. The ic acid or ylic acid salt of the compound of Claim 14, wherein the pharmaceutically acceptable salt of said nd is a substantially pure (E) or (Z) .

20. The amorphous form of the pharmaceutically acceptable salt of the compound of any one of Claims 15-18, wherein the pharmaceutically acceptable salt of said compound is a substantially pure (E) or (Z) .

21. The sulfonic acid or carboxylic acid salt of the compound of Claim 19, wherein at least about 80% w/w of the salt of the compound is the (E) isomer, preferably wherein at least about 90% w/w of the pharmaceutically acceptable salt of the compound is the (E) isomer.

22. The amorphous form of the ceutically acceptable salt of the compound of Claim 20, wherein at least about 80% w/w of the pharmaceutically acceptable salt of the nd is the (E) isomer, preferably wherein at least about 90% w/w of the pharmaceutically acceptable salt of the compound is the (E) isomer.

23. A pharmaceutical composition comprising the sulfonic acid or carboxylic acid salt of any one of Claims 14, 19 and 21 or the amorphous form of a pharmaceutically acceptable salt of the compound of any one of Claims 15-18, 20 and 22.

24. A method of treating pemphigus is in a non-human mammal in need of such treatment, which method comprises administering to the man mammal the pharmaceutical ition of Claim 23.

25. Use of the pharmaceutical composition of Claim 23 for the manufacture of a medicament for treating pemphigus vulgaris.

26. A method according to any one of claims 1-3 or 24 or a use according to any one of claims 7- 9 or 25, substantially as herein described with reference to any one or more of the examples but excluding comparative examples.

27. A sulfonic acid or carboxylic acid salt of a compound according to claim 14, substantially as herein described with nce to any one or more of the examples but excluding comparative examples.

28. An amorphous form of a pharmaceutically able salt of a compound according to claim 15, substantially as herein described with reference to any one or more of the examples but excluding comparative examples.

29. A pharmaceutical composition according to claim 23, substantially as herein described with reference to any one or more of the examples but excluding ative examples.