FIELD OF THE INVENTION

The present invention relates to crystalline Form A of (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide, hereafter "Compound (I)", and particular crystalline salt forms of Compound (I), more particularly to the Form A mesitylene sulphonic acid salt of Compound (I), the Form B malonate salt of Compound (I) and the Form A tartrate salt of Compound (I). The crystalline Form A of Compound (I) free base, the Form A mesitylene sulphonic acid salt of Compound (I), the Form B malonate salt of Compound (I) and the Form A tartrate salt of Compound (I) are expected to be useful for the treatment or prophylaxis of conditions mediated alone or in part by Bruton

Tyrosine Kinase (BTK), particularly hyperproliferative diseases such as cancers, inflammation, immune, and autoimmune diseases. The invention also relates to a pharmaceutical composition comprising the crystalline Compound (I) free base Form A, the Form A mesitylene salt of Compound (I), the Form B malonate salt of Compound (I) or the Form A tartrate salt of

Compound (I) and to their use in the treatment or prophylaxis of diseases mediated by BTK, such as cancer, inflammation, immune, and autoimmune diseases.

In some embodiments, the invention relates to crystalline Form A of (S)-4-(8-amino-3-(l- but-2-ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-met hoxy-N-(pyridin-2-yl)benzamide. In other embodiments, the invention relates to crystalline mesitylene sulphonic acid salt of (S)-4- (8-amino-3-(l-but-2-ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyraz in-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide Form A. In other embodiments, the invention relates to crystalline (S)-4-(8-amino- 3-(l-but-2-ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)- 2-methoxy-N-(pyridin-2- yl)benzamide malonate Form B. In other embodiments, the invention relates to crystalline (S)-4- (8-amino-3-(l-but-2-ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyraz in-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide tartrate Form A. In other embodiments, the invention relates to pharmaceutical compositions comprising Compound (I) free base Form A, Compound (I) mesitylene sulphonic acid salt Form A, Compound (I) malonate Form B or Compound (I) tartrate Form A, and methods for treating cancers or other disorders by administering the pharmaceutical

compositions to a subject. BACKGROUND OF THE INVENTION

Bruton Tyrosine Kinase (BTK) [also referred to in the art as Bruton's tyrosine kinase] is a Tec family non-receptor protein kinase expressed in B cells and myeloid cells. BTK is composed of the pleckstrin homology (PH), Tec homology (TH), Src homology 3 (SH3), Src homology 2 (SH2), and tyrosine kinase or Src homology 1 (TK or SHI) domains. The function of BTK in signaling pathways activated by the engagement of the B cell receptor (BCR) in mature B cells and FCER1 on mast cells is well established. Functional mutations in BTK in humans result in a primary immunodeficiency disease (X-linked agammaglobulinemia) characterized by a defect in B cell development with a block between pro- and pre-B cell stages. The result is an almost complete absence of B lymphocytes, causing a pronounced reduction of serum immunoglobulin of all classes. These findings support a key role for BTK in the regulation of the production of auto-antibodies in autoimmune diseases.

BTK is expressed in numerous B cell lymphomas and leukemias. Other diseases with an important role for dysfunctional B cells are B cell malignancies, as described in Hendriks, et ah, Nat. Rev. Cancer, 2014, 14, 219-231. The reported role for BTK in the regulation of

proliferation and apoptosis of B cells indicates the potential for BTK inhibitors in the treatment of B cell lymphomas. BTK inhibitors have thus been developed as potential therapies for many of these malignancies, as described in D'Cruz, et ah, OncoTargets and Therapy 2013, 6, 161- 176.

Compound (I) is a BTK inhibitor disclosed in International Patent Application

Publication number WO2013/010868 as Example 99 and is isolated therein as the free base. There is no disclosure in WO2013/010868 of any specific crystalline polymorph or salt of Compound (I). Compound (I) in WO2013/010868 is of the structure:

Compound (I)

Acid-reducing agents can greatly limit the exposure of weakly basic drugs (such as Compound (1) free base) in mammals. Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055-4062. Acid reducing agents include proton pump inhibitors, such as omeprazole, esomeprazole and lansoprazole; H ₂ receptor antagonists, such as cimetidine, ranitidine, and famotidine; and antacids such as bicarbonates, carbonates, and hydroxides of aluminium, as well as mixtures of antacids with agents targeting mechanisms of gastric secretion. Overcoming the effects of acid reducing agents is a significant issue in the treatment of patients with cancer, inflammatory diseases, immune diseases, and autoimmune diseases, since these patients are commonly co-administered acid reducing agents for gastric irritation that often accompanies their conditions. Acid reducing agents are the most commonly prescribed medications in North America and Western Europe. Most recently approved oral cancer therapeutics have pH-dependent solubility and thus a potential drug-drug interaction with regards to acid reducing agents. In cancer patients, it is estimated that 20-33% of all patients are using some form of acid-reducing agent. In particular cancers, such as pancreatic cancer or gastrointestinal cancers, acid reducing agent use is as high as 60-80% of patients. Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055-4062.

The present invention includes novel crystalline solid Form A of (S)-4-(8-amino-3-(l- but-2-ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-met hoxy-N-(pyridin-2-yl)benzamide.

The present invention includes novel crystalline solid Form A of (S)-4-(8-amino-3-(l- but-2-ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-met hoxy-N-(pyridin-2-yl)benzamid mesitylene sulphonic acid salt, referred to herein as Compound (I) mesitylene sulphonic acid salt Form A.

The present invention includes novel crystalline solid Form B of (S)-4-(8-amino-3-(l-but- 2-ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy -N-(pyridin-2-yl)benzamide malonate, referred to herein as Compound (I) malonate Form B.

The present invention includes novel crystalline solid Form A of (S)-4-(8-amino-3-(l- but-2-ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-met hoxy-N-(pyridin-2-yl)benzamide tartrate, referred to herein as Compound (I) tartrate Form A.

The novel salt forms of Compound (I) claimed herein (e.g. mesitylene sulphonic acid salt Form A, malonate Form B and tartrate Form A), have one or more favourable properties compared to Compound (I) free base and/or other salt forms.

The novel mesitylene sulphonic acid, malonate and tartrate salt forms claimed herein show greatly improved in vitro dissolution rates at elevated pH: at 15 minutes the dissolved concentrations are 6 to 7 fold higher than that of the free base and roughly two-fold higher than the fumarate and citrate salts, as can be seen in Figure 30. The novel mesitylene sulphonic acid, malonate and tartrate salt forms claimed herein also stay supersaturated for more than 3 hours at 37 °C, pH 5 as can be seen in Figure 31. This increased dissolution rate and supersaturation will likely lead to greater exposure in patients having higher gastric pH. The novel mesitylene sulphonic acid, malonate and tartrate salt forms claimed herein are also expected to show a reduced food effect on gastrointestinal (GI) absorption compared with the free base and the fumarate and citrate salts.

SUMMARY OF THE INVENTION

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide Form A.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt Form A.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide malonate Form B.

In an embodiment, the invention provides a composition comprising crystalline (S)-4-(8- amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide Form A.

In an embodiment, the invention provides a composition comprising crystalline (S)-4-(8- amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide mesitylene sulphonic acid salt Form A.

In an embodiment, the invention provides a composition comprising crystalline (S)-4-(8- amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide malonate Form B.

In an embodiment, the invention provides a composition comprising crystalline (S)-4-(8- amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide tartrate Form A.

In an embodiment, the invention provides a method of treating a hyperproliferative disease comprising the step of administering a therapeutically effective amount of a composition selected from the group consisting of: (i) a composition comprising crystalline (S)-4-(8-amino-3- (l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide Form A; (ii) a composition comprising crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt Form A; (iii) a composition comprising crystalline (S)-4-(8- amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide malonate Form B; and. (iv) a composition comprising crystalline (S)-4-(8-amino- 3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide fumarate Form A, to a mammal, wherein the hyperproliferative disease is selected from the group consisting of chronic lymphocytic leukemia, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoproliferative disease, B cell acute lymphoblastic leukemia, Waldenstrom's macroglobulinemia, Burkitt's leukemia, Hodgkin's disease, multiple myeloma, acute myeloid leukemia, juvenile

myelomonocytic leukemia, hairy cell leukemia, mast cell leukemia, mastocytosis,

myeloproliferative disorders (MPDs), myeloproliferative neoplasms, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), myelodysplasia syndrome, chronic myelogenous leukemia (BCR-ABLl-positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, primary central nervous system (CNS) lymphoma, primary multifocal lymphoma of peripheral nervous system (PNS), thymus cancer, brain cancer, glioblastoma, lung cancer, squamous cell cancer, skin cancer (e.g., melanoma), eye cancer, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal cancers, bladder cancer, gastric cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer, head and neck cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer (e.g., metastatic bone cancer), esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, epidermoid cancer, AIDS-related cancer (e.g., lymphoma), viral-induced cervical carcinoma (human papillomavirus), nasopharyngeal carcinoma (Epstein-Barr virus), Kaposi' s sarcoma, primary effusion lymphoma (Kaposi's sarcoma herpesvirus), hepatocellular carcinoma (hepatitis B and hepatitis C viruses), T-cell leukemias (Human T-cell leukemia virus-1), benign hyperplasia of the skin, restenosis, benign prostatic hypertrophy, tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcet' s disease, polymyalgia rheumatica, giant- cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, lupus, and lupus nephritis.

In an embodiment, the invention provides a method of treating a hyperproliferative disease comprising the step of administering a therapeutically effective amount of a composition selected from the group consisting of: (i) a composition comprising crystalline (S)-4-(8-amino-3- (l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide Form A; (ii) a composition comprising crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin- l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt Form A; (iii) a composition comprising crystalline (S)-4-(8- amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide malonate Form B; and (iv) a composition comprising crystalline (S)-4-(8-amino-3- (l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide fumarate Form A, to a mammal, wherein the hyperproliferative disease is selected from the group consisting of lupus, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenstrom's macroglobulinemia.

In an embodiment, the invention provides a method of treating a hyperproliferative disease comprising the step of administering a therapeutically effective amount of a composition selected from the group consisting of: (i) a composition comprising crystalline (S)-4-(8-amino-3- (l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide Form A; (ii) a composition comprising crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt Form A; (iii) a composition comprising crystalline (S)-4-(8- amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide malonate Form B; and (iv) a composition comprising crystalline (S)-4-(8-amino-3- (l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide fumarate Form A, to a human, wherein the hyperproliferative disease is selected from the group consisting of lupus, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenstrom's macroglobulinemia. BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings.

For all the XRPD figures the x-axis shows the 2-theta value and the y-axis the intensity counts.

For the figures comprising DSC traces, the x-axis shows the temperature ( ^° C) and the y- axis the heat flow (W/g).

For the figures comprising TGA traces, the x-axis shows the temperature ( ^° C) and y-axis the weight change (%).

Figure 1 shows an X-ray powder diffraction pattern (XRPD) for Compound (I) free base Form A. Figure 2 shows a differential scanning calorimetry (DSC) and thermogravimetry analysis (TGA) traces on Compound (I) free base Form A.

Figure 3 shows the XRPD pattern for Compound (I) free base Form B.

Figure 4 shows the DSC and TGA traces of Compound (I) free base Form B.

Figure 5 shows the XRPD pattern for Compound (I) mesitylene sulphonic acid salt Form

A.

Figure 6 shows the DSC trace for Compound (I) mesitylene sulphonic acid salt Form A.

Figure 7 shows the XRPD pattern for Compound (I) malonate (Form A).

Figure 8 shows the XRPD pattern for Compound (I) malonate (Form B).

Figure 9 shows the DSC and TGA traces of Compound (I) malonate (Form B).

Figure 10 shows the XRPD pattern for Compound (I) malonate (Form C).

Figure 11 shows the DSC and TGA traces of Compound (I) malonate (Form B).

Figure 12 shows the XRPD pattern for Compound (I) citrate (Form A).

Figure 13 shows the DSC and TGA traces of Compound (I) citrate (Form A).

Figure 14 shows the XRPD pattern for Compound (I) citrate (Form B).

Figure 15 shows the DSC and TGA traces of Compound (I) citrate (Form B).

Figure 16 shows the XRPD pattern for Compound (I) tartrate (Form A).

Figure 17 shows the DSC and TGA traces of Compound (I) tartrate (Form A).

Figure 18 shows the XRPD pattern for Compound (I) tartrate (Form B).

Figure 19 shows the XRPD pattern for Compound (I) tartrate (Form C).

Figure 20 shows the XRPD pattern for Compound (I) fumarate (Form A).

Figure 21 shows the DSC and TGA traces of Compound (I) fumarate (Form A).

Figure 22 shows the XRPD pattern for Compound (I) fumarate (Form B).

Figure 23 shows the DSC and TGA traces of Compound (I) fumarate (Form B).

Figure 24 shows the XRPD pattern for Compound (I) fumarate (Form C).

Figure 25 shows the XRPD pattern for Compound (I) malate (Form A).

Figure 26 shows the DSC and TGA traces of Compound (I) malate (Form A).

Figure 27 shows the XRPD pattern for Compound (I) malate (Form B).

Figure 28 shows the XRPD pattern for Compound (I) malate (Form C).

Figure 29 shows the XRPD pattern for Compound (I) malate (Form D)

Figure 30 shows concentration (mg/mL) in solution at pH 5 over time of free base and salts measured by LC-UV. Top to bottom at 15 minutes; ^x mesitylene sulfonic acid salt Form

A, □ malonate Form B, ® tartrate Form A , O fumarate Form B, ^Δ citrate Form A, ⁺ free base Form A.

Figure 31 shows Concentration (mg/mL) in solution at pH 5 over time of free base and salts measured by online UV. Top to bottom at 30 minutes; ·« · ··.. mesitylene sulfonic acid salt Form A, malonate Form B, ^** " "tartrate Form A, ~~ ^{' ' "} citrate form A, fumarate Form B, free base Form A.

DETAILED DESCRIPTION OF THE INVENTION

While certain embodiments of the invention are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the invention.

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entireties.

The terms "co-administration," "co-administering," "administered in combination with," and "administering in combination with" as used herein, encompass administration of two or more agents to a subject so that both agents and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate

compositions, administration at different times in separate compositions, or administration in a composition in which two or more agents are present.

The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g., the reduction of platelet adhesion and/or cell migration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

The terms "QD," "qd," or "q.d." mean quaque die, once a day, or once daily. The terms "BID," "bid," or "b.i.d." mean bis in die, twice a day, or twice daily. The terms "TID," "tid," or "t.i.d." mean ter in die, three times a day, or three times daily. The terms "QID," "qid," or "q.i.d." mean quater in die, four times a day, or four times daily.

A "therapeutic effect" as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

The term "acidulant" refers to a substance that increases acidity.

The terms "transmission" or "transmission mode," when used in conjunction with powder X-ray diffraction, refers to the transmission (also known as Debye-Scherrer) sampling mode. The terms "reflection" or "reflection mode," when used in conjunction with powder X-ray diffraction, refers to the reflection (also known as Bragg-Brentano) sampling mode.

Unless otherwise stated, the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by ¹³ C- or ¹⁴ C-enriched carbons, are within the scope of this invention.

When ranges are used herein to describe, for example, physical or chemical properties such as molecular weight of chemical compounds, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Use of the term "about" or "approximately" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments such as, for example, an embodiment of any composition of matter, method or process that "consist of or "consist essentially of the described features.

Crystalline Forms

Two distinct crystalline forms (polymorphs) of the free base were identified. Form B is a hydrate with relatively poor solid-state properties (poor crystallinity and stability). Form A however, is anhydrous and showed good crystallinity and stability. As an anhydrate, the Form A polymorph of Compound (I) is expected to have an increased aqueous solubility over the crystalline hydrated Form B.

In an embodiment, the invention provides a crystalline solid Form A of (S)-4-(8-amino-3- (l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide.

(S)-4-(8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5 - ]pyrazin-l-yl)-2- methoxy-N-(pyridin-2-yl)benzamide that is referred to herein as Compound (1) has the following chemical structure:

Compound (I)

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide Form A, characterized by an X-ray powder diffraction pattern with at least one peak at about 2-theta = 7.9°.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide Form A, characterized by an X-ray powder diffraction pattern with at least one peak at about 2-theta = 10.0°.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide Form A, characterized by an X-ray powder diffraction pattern with at least one peak at about 2-theta = 14.6°.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide Form

A, characterised by an X-ray powder diffraction pattern with at least two peaks at 2-theta selected from: 7.9° ± 0.2 °2Θ, 10.0° ± 0.2 °2Θ and 14.6° ± 0.2 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide Form

A, characterised by an X-ray powder diffraction pattern with at least three peaks at 2-theta selected from: 7.9° ± 0.1 °2Θ, 10.0° ± 0.1 °2Θ and 14.6° ± 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide Form A, characterised by an X-ray powder diffraction pattern with at least three peaks at 2-theta: 7.9°

± 0.2 °2Θ, 10.0° ± 0.2 °2Θ and 14.6° ± 0.2 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide Form

A, characterised by an X-ray powder diffraction pattern with at least three peaks at 2-theta: 7.9° ± 0.1 °2Θ, 10.0° ± 0.1 °2Θ and 14.6° ± 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide Form

A, characterized by an X-ray powder diffraction pattern with peaks at 2-theta: 7.9 ± 0.2 °2Θ,

10.0° ± 0.2 °2Θ, 14.6° ± 0.2 °2Θ, 6.2° ± 0.2 °2Θ and 20.0 ± 0.2 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide Form A, characterized by an X-ray powder diffraction pattern with peaks at 2-theta: 7.9° ± 0.1 °2Θ, 10.0° ± 0.1 °2Θ, 14.6° ± 0.1 °2Θ, 6.2° ± 0.1 °2Θ and 20.0° ± 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide Form A, wherein said Form A has an X-ray powder diffraction pattern with peaks at about 2-theta = 10.0°, 24.0°, 25.9°, 14.6°, 16.9°, 20.0°, 13.9°, 6.2°, 12.3° and 7.9°.

It is known in the art that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or instrument used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may vary depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realise that the relative intensities of peaks may vary according to the orientation of the sample under test and based on the type and settings of the instrument used. The skilled person will also realise that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer, the sample's surface planarity, and the zero calibration of the diffractometer. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a power diffraction pattern substantially the same as those disclosed herein fall within the scope of the present disclosure. For further information, see Jenkins and Snyder, Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, 1996.

To allow for usual experimental variation, each of the XRPD peaks recited herein to identify a particular crystalline form of Compound (I), including salt forms thereof, can be plus or minus 0.2 °2Θ. In some embodiments, each of the XRPD peaks recited herein to identify a particular crystalline form of Compound (I), including salt forms thereof, can be plus or minus 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide (Form A), characterized by an X-ray powder diffraction pattern substantially in agreement with the X- ray powder diffraction pattern of FIG. 1. The XRPD shown in Fig. l was measured in reflection mode. In an embodiment, the X-ray powder diffraction pattern of any of the foregoing embodiments is measured in reflection mode. Form A has an endotherm event of melting/decomposition with an onset at 232 °C and a peak at 235 °C. Thus, in an embodiment, the invention provides crystalline (S)-4-(8-amino-3- (l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide (Form A), characterized by a melting point of about 232°C± 1°C.

We have found that the crystalline Form A of Compound (I) free base has favourable properties compared to other crystalline forms of the Compound (I) free base and/or salt forms of Compound (I), for example, Compound (I) Form A free base exhibits high crystallinity, reduced hygroscopicity, and/or favourable thermal properties (such as a high melting point). Crystalline Salt Forms.

Mesitylene sulphonic acid salt.

In an embodiment, the invention provides a crystalline solid form of (S)-4-(8-amino-3-(l-

(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt (Form A), characterized by an X-ray powder diffraction pattern with at least one peak at about 2-theta = 21.9°.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt (Form A), characterized by an X-ray powder diffraction pattern with at least one peak at about 2-theta = 7.3°.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide mesitylene sulphonic acid salt Form A, characterised by an X-ray powder diffraction pattern with at least two peaks at 2-theta = 21.9° ± 0.2 °2Θ and 7.3° ± 0.2 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide mesitylene sulphonic acid salt Form A, characterised by an X-ray powder diffraction pattern with at least two peaks at 2-theta = 21.9° ± 0.1 °2Θ and 7.3° ± 0.1 °2Θ. In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide mesitylene sulphonic acid salt Form A, characterized by an X-ray powder diffraction pattern with at least four peaks at 2-theta = 7.3° ± 0.2 °2Θ, 10.9° ± 0.2 °2Θ, 13.1° ± 0.2 °2Θ and 28.3° ± 0.2 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide mesitylene sulphonic acid salt Form A, characterized by an X-ray powder diffraction pattern with at least four peaks at 2-theta = 7.3° ± 0.1 °2Θ, 10.9° ± 0.1 °2Θ, 13.1° ± 0.1 °2Θ and 28.3° ± 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide mesitylene sulphonic acid salt Form A, characterised by an X-ray powder diffraction pattern with peaks at 2-theta = 21.9°, 7.3°, 14.2°, 21.2°, 14.0°, 22.3°, 28.3°, 13.1°, 10.0° and 14.6°, each peak ± 0.2 °2Θ, , or in some embodiments, each peak at ± 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt (Form A), characterized by an X-ray powder diffraction pattern substantially in agreement with the X-ray powder diffraction pattern of FIG. 5. The XRPD shown in Fig. 5 was measured in reflection mode. In an embodiment, the X-ray powder diffraction pattern of any of the foregoing embodiments is measured in reflection mode.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt (Form A), characterized by an onset of melting at about 229.9°C and a peak at about 234.1°C as measured using DSC. In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5 - ]pyrazin-l-yl)-2- methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt (Form A), characterized by having a melting point at about 230°C ± 1°C. Crystalline (S)-4-(8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5 - ]pyrazin-l- yl)-2-methoxy-N-(pyridin-2-yl)benzamide mesitylene sulphonic acid salt Form A provides one or more advantages over the (S)-4-(8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5 - ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide free base and/or other salt forms of the compound, including a more favourable in vitro dissolution profile, improved chemical stability, reduced hygroscopicity, and/or improved thermodynamic stability. Further, based on the in vitro dissolution experiments at pH 5.0, it is predicted that this salt form may have improved performance in the stomach and gastric environment of patients with elevated gastric pH.

Malonate-Form B

In an embodiment, the invention provides a crystalline solid form of (S)-4-(8-amino-3-(l- (but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide malonate Form B.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide malonate Form B, characterized by an X-ray powder diffraction pattern with at least one peak at about 2-theta = 8.7°.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide malonate Form B, characterized by an X-ray powder diffraction pattern with at least one peak at about 2-theta = 9.4°.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide malonate Form B, characterized by an X-ray powder diffraction pattern with at least one peak at about 2-theta = 13.6°.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide malonate Form B, characterised by an X-ray powder diffraction pattern with at least three peaks at 2-theta = 8.7°± 0.2 °2Θ, 9.4° ± 0.2 °2Θ and 13.6° ± 0.2 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide malonate Form B, characterised by an X-ray powder diffraction pattern with at least three peaks at 2-theta = 8.7°± 0.1 °2Θ, 9.4° ± 0.1 °2Θ and 13.6° ± 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide malonate Form B, characterized by an X-ray powder diffraction pattern with peaks at 2-theta = 8.7°± 0.2 °2Θ, 9.4° ± 0.2 °2Θ, 13.6° ± 0.2 °2Θ, 16.0° ± 0.2 °2Θ and 16.9° ± 0.2 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide malonate Form B, characterized by an X-ray powder diffraction pattern with peaks at 2-theta = 8.7° ± 0.1 °2Θ, 9.4° ± 0.1 °2Θ, 13.6° ± 0.1 °2Θ, 16.0° ± 0.1 °2Θ and 16.9° ± 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide malonate Form B, characterised by an X-ray powder diffraction pattern with peaks at 2-theta = 8.7°, 13.6°, 9.4°, 26.4°, 18.9°, 23.6°, 16.9°, 24.4°, 16.0° and 22.2°, each peak ± 0.2 °2Θ, or in some embodiments, each peak ± 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide malonate Form B, characterized by an X-ray powder diffraction pattern substantially in agreement with the X-ray powder diffraction pattern of FIG. 8. The XRPD shown in Fig. 8 was measured in reflection mode. In an embodiment, the X-ray powder diffraction pattern of any of the foregoing embodiments is measured in reflection mode.

Compound (I) malonate Form B has an endotherm event of desolvation with an onset at 34 °C and a peak at 74 °C. Additional endotherm event of melting/decomposition with an onset at 131 °C and a peak at 139 °C is also identified. Thus, in an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5 - ]pyrazin-l-yl)-2- methoxy-N-(pyridin-2-yl)benzamide malonate Form B, characterized by an endotherm event of desolvation with an onset at about 34 °C and a peak at about 74 °C. In a further embodiment, the Form B also has an additional endotherm event of melting/decomposition with an onset at about 131 °C and a peak at about 139 °C.

Crystalline (S)-4-(8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5 - ]pyrazin-l- yl)-2-methoxy-N-(pyridin-2-yl)benzamide malonate Form B provides one or more advantages over the (S)-4-(8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5 - ]pyrazin-l-yl)-2- methoxy-N-(pyridin-2-yl)benzamide free base and/or other salt forms of the compound, including a more favourable in vitro dissolution profile, improved chemical stability, reduced hygroscopicity, and/or improved thermodynamic stability. Further, based on the in vitro dissolution experiments at pH 5.0, it is predicted that this salt form may have improved performance in the stomach and gastric environment of patients with elevated gastric pH.

Tartrate-Form A

In an embodiment, the invention provides a crystalline solid form of (S)-4-(8-amino-3-(l-

(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide tartrate Form A.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide tartrate Form A, characterized by an X-ray powder diffraction pattern with at least one peak at about 2-theta = 8.0°.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide tartrate Form A, characterized by an X-ray powder diffraction pattern with at least one peak at about 2-theta = 11.0°.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide tartrate Form A, characterized by an X-ray powder diffraction pattern with at least two peaks at 2-theta = 8.0°± 0.2 °2Θ and 11.0° ± 0.2 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide tartrate Form A, characterized by an X-ray powder diffraction pattern with at least two peaks at 2-theta = 8.0°± 0.1 °2Θ and 11.0° ± 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide tartrate Form A, characterized by an X-ray powder diffraction pattern with peaks at 2-theta = 8.0°± 0.2 °2Θ, 11.0°± 0.2 °2Θ , 12.2°+ 0.2 °2Θ and 18.3° ± 0.2 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide tartrate Form A, characterized by an X-ray powder diffraction pattern with peaks at 2-theta = 8.0° ± 0.1 °2Θ, 11.0° ± 0.1 °2Θ, 12.2° ± 0.1 °2Θ and 18.3° ± 0.1 °2Θ. In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-but-2- ynoylpyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N -(pyridin-2-yl)benzamide tartrate Form A, characterized by an X-ray powder diffraction pattern with peaks at 2-theta = 6.5°, 12.2°, 24.5°, 11.0°, 22.1°, 27.1°, 18.3°, 13.5°, 16.1° and 8.0°, each peak ± 0.2 °2Θ, or in some embodiments, each peak ± 0.1 °2Θ.

In an embodiment, the invention provides crystalline (S)-4-(8-amino-3-(l-(but-2- ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)benzamide tartrate Form A, characterized by an X-ray powder diffraction pattern substantially in agreement with the X-ray powder diffraction pattern of FIG. 16. The XRPD shown in Fig. 16 was measured in reflection mode. In an embodiment, the X-ray powder diffraction pattern of any of the foregoing embodiments is measured in reflection mode.

Compound (I) tartrate Form A has a broad endotherm event of desolvation with an onset at 59°C and a peak at 97°C. Additional endotherm event of melting with an onset at 156°C and a peak at 172°C is also observed. Thus, in an embodiment, the invention provides crystalline (S)-4- (8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5- ]pyrazin-l-yl)-2-methoxy-N-(pyridin- 2-yl)benzamide tartrate Form A, characterized by a broad endotherm event of desolvation with an onset at about 59°C and a peak at about 97°C. In a further embodiment, the tartrate Form A also has an additional endotherm event of melting with an onset at about 156°C and a peak at about 172°C.

Crystalline (S)-4-(8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5 - ]pyrazin-l- yl)-2-methoxy-N-(pyridin-2-yl)benzamide tartrate Form A provides one or more advantages over the (S)-4-(8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5 - ]pyrazin-l-yl)-2-methoxy-N- (pyridin-2-yl)benzamide free base and/or other salt forms of the compound, including a more favourable in vitro dissolution profile, improved chemical stability, reduced hygroscopicity, and/or improved thermodynamic stability. Further, based on the in vitro dissolution experiments at pH 5.0, it is predicted that this salt form may have improved performance in the stomach and gastric environment of patients with elevated gastric pH.

Pharmaceutical Compositions

The compounds of the invention may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the Compound (I) free base Form A or salt (e.g. Compound (I) mesitylene sulphonic acid salt Form A, Compound (I) malonate Form B or Compound (I) tartrate Form A), as active ingredient, is in association with or mixed in with a pharmaceutically acceptable excipient.

Typically, the pharmaceutical compositions are formulated to provide a therapeutically effective amount of a solid form of the BTK inhibitor, as the active ingredient. Where desired, the pharmaceutical compositions contain one or more pharmaceutically acceptable excipients.

In an embodiment, the invention provides a pharmaceutical composition comprising crystalline Form A of Compound (1) free base and a pharmaceutically acceptable excipient.

In an embodiment, the invention provides a pharmaceutical composition comprising crystalline Compound (1) mesitylene sulphonic acid salt Form A and a pharmaceutically acceptable excipient.

In an embodiment, the invention provides a pharmaceutical composition comprising crystalline Compound (1) malonate Form B and a pharmaceutically acceptable excipient.

In an embodiment, the invention provides a pharmaceutical composition comprising crystalline Compound (1) tartrate Form A and a pharmaceutically acceptable excipient.

The excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth edition,

Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian.

Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, solubilizers, permeation enhancers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

In one embodiment, the invention provides a process for the preparation of a

pharmaceutical composition of the disclosure which comprises mixing Compound (I) free base Form A, or a Compound (I) salt (e.g. mesitylene sulphonic acid salt Form A, malonate Form B or tartrate Form A), as hereinbefore defined with one or more pharmaceutically acceptable excipients.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

In some embodiments, the concentration of the particular solid form of Compound (1) (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) provided in the pharmaceutical compositions of the invention is independently less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, or 0.001% w/w, w/v, or v/v, relative to the total mass or volume of the pharmaceutical composition.

In some embodiments, the concentration of the particular solid form of Compound (1) (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) provided in the pharmaceutical compositions of the invention is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, or 0.001% w/w, w/v, or v/v, relative to the total mass or volume of the pharmaceutical composition.

In some embodiments, the concentration of the particular solid form of Compound (1)

(e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) provided in the pharmaceutical compositions of the invention is independently in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to

approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12% or approximately 1% to approximately 10% w/w, w/v or v/v, relative to the total mass or volume of the pharmaceutical composition.

In some embodiments, the concentration of the particular solid form of Compound (1) (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) provided in the pharmaceutical compositions of the invention is independently in the range from approximately 0.001% to approximately 10%, approximately 0.01% to

approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v, or v/v, relative to the total mass or volume of the pharmaceutical composition.

In some embodiments, the amount of the particular solid form of Compound (1) (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) provided in the pharmaceutical compositions of the invention is independently equal to or less than 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g.

In some embodiments, the amount of the particular solid form of Compound (1) (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) provided in the pharmaceutical compositions of the invention is independently equal to or less than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5g, or 3 g.

The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler ^® ; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous,

intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories.

For oral administration the compound of the disclosure may be admixed with one or more excipients, e.g. adjuvant(s), diluent(s) or carrier(s), such as lactose, saccharose, sorbitol, mannitol; starch, for example, potato starch, corn starch or amylopectin; cellulose derivative; binder, for example, gelatine or polyvinylpyrrolidone; disintegrant, for example cellulose derivative, and/or lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s). Alternatively, the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.

For the preparation of soft gelatine capsules, the compound of the disclosure may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using pharmaceutical excipients like the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the disclosure may be filled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups, solutions or suspensions. Solutions, for example may contain the compound of the disclosure, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharine and/or

carboxymethylcellulose as a thickening agent. Furthermore, other excipients known to those skilled in art may be used when making formulations for oral use.

In selected embodiments, there is provided a pharmaceutical composition for oral administration containing a particular solid form of Compound (1) (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) according to the invention and a pharmaceutical excipient suitable for oral administration.

In selected embodiments, there is provided a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a particular solid form of Compound (1) (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) according to the invention, and (ii) a pharmaceutical excipient suitable for oral administration. In selected embodiments, the composition further contains (iii) an effective amount of another active pharmaceutical ingredient.

In selected embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, sachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or nonaqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion. Pharmaceutical

compositions of the invention also include powder for reconstitution, powders for oral consumptions, bottles (such as powder or liquid in bottle), orally dissolving films, lozenges, pastes, tubes, gums, and packs. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients. In general, the

compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The invention further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical

composition may be prepared and stored such that its anhydrous nature is maintained.

Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable dry kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

Each of the solid forms of the BTK inhibitor of Compound (1) (e.g. Form A free base,

Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) according to the invention can be combined in an intimate admixture with a pharmaceutical excipient according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, glidants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Dosages and Dosing Regimens

The compound of the invention (e.g. Compound (I) free base Form A, Compound (I) mesitylene sulphinic acid salt Form A, Compound (I) malonate Form B or Compound (I) tartrate Form A) is expected to be effective over a wide dosage range. For example, in the treatment of adult humans, dosages independently range from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, from 2 to 40 mg per day, and from 5 to 25 mg per day are examples of dosages that may be used. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

The amounts of the solid form of Compound (1) according to the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, for example by dividing such larger doses into several small doses for administration throughout the day.

In selected embodiments, a solid form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) is administered in a single dose. Typically, such administration will be by injection, for example by intravenous injection, in order to introduce the active pharmaceutical ingredients quickly. However, other routes may be used as appropriate. A single dose of a solid form of crystalline Compound (1) of the invention may also be used for treatment of an acute condition.

In selected embodiments, a solid form of the Compound (1) (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In other embodiments, a solid form of the Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) is administered about once per day to about 6 times per day. In another embodiment the administration of the solid form of the Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

Administration of the active pharmaceutical ingredients of the invention may continue as long as necessary. In selected embodiments, the particular crystalline solid form of Compound (1) (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a solid form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In selected embodiments, the solid form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) is administered chronically on an ongoing basis - e.g., for the treatment of chronic effects.

In some embodiments, an effective dosage of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 to about 202 mg. In some embodiments, an effective dosage of a solid form of the BTK inhibitor of Compound (1) is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In some embodiments, an effective dosage of Compound (1) mesitylene sulphonic acid salt is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg. In some embodiments, an effective dosage of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) is in the range of about 0.01 mg/kg to about 4.3 mg/kg, about 0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about 3.2 mg/kg, about 0.35 mg/kg to about 2.85 mg/kg, about 0.15 mg/kg to about 2.85 mg/kg, about 0.3 mg to about 2.15 mg/kg, about 0.45 mg/kg to about 1.7 mg/kg, about 0.15 mg/kg to about 1.3 mg/kg, about 0.3 mg/kg to about 1.15 mg/kg, about 0.45 mg/kg to about 1 mg/kg, about 0.55 mg/kg to about 0.85 mg/kg, about 0.65 mg/kg to about 0.8 mg/kg, about 0.7 mg/kg to about 0.75 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg, about 0.85 mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85 mg/kg, about 1.15 mg/kg to about 1.7 mg/kg, about 1.3 mg/kg mg to about 1.6 mg/kg, about 1.35 mg/kg to about 1.5 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kg to about 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6 mg/kg to about 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about 2.8 mg/kg to about 3 mg/kg, or about 2.85 mg/kg to about 2.95 mg/kg. In some embodiments, an effective dosage of Compound (1) mesitylene sulphonic acid salt is about 0.35 mg/kg, about 0.7 mg/kg, about 1 mg/kg, about 1.4 mg/kg, about 1.8 mg/kg, about 2.1 mg/kg, about 2.5 mg/kg, about 2.85 mg/kg, about 3.2 mg/kg, or about 3.6 mg/kg.

In some embodiments, the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) is administered at a dosage of 10 to 400 mg once daily (QD), including a dosage of 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg once daily (QD).

In some embodiments, the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) is administered at a dosage of 10 to 400 mg BID, including a dosage of 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg BID.

In some embodiments, the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) is administered at a dosage of 10 to 400 mg TID, including a dosage of 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg TID.

An effective amount of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) may be administered in either single or multiple doses by any of the accepted modes of administration of active pharmaceutical ingredients having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra- arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

The compounds, compositions and methods described herein can be used to overcome the effects of acid reducing agents. Acid-reducing agents can greatly limit the exposure of weakly acidic drugs (such as Compound (1) free base) in mammals. Smelick, et ah, Mol. Pharmaceutics 2013, 10, 4055-4062. Acid reducing agents include proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole; H ₂ receptor antagonists, such as cimetidine, ranitidine, and famotidine; and antacids such as bicarbonates, carbonates, and hydroxides of aluminium, calcium, magnesium, potassium, and sodium, as well as mixtures of antacids with agents targeting mechanisms of gastric secretion.

Methods of Treating Solid Tumor Cancers, Hematological Malignancies, Inflammatory

Diseases, Autoimmune Disorders, Immune Disorders, and Other Diseases

The compounds and pharmaceutical compositions described herein can be used in a method for treating diseases. In particular embodiments, they are for use in treating

hyperproliferative disorders. They may also be used in treating other disorders as described herein and in the following paragraphs.

In some embodiments, the invention provides a method of treating a hyperproliferative disorder in a mammal that comprises administering to the mammal a therapeutically effective amount of a crystalline solid form of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate), or a pharmaceutical composition comprising a crystalline solid form of the particular form of Compound (1) of the invention, as described herein. In particular embodiments, the mammal is a human. In some embodiments, the hyperproliferative disorder is cancer. In certain

embodiments, the cancer is selected from the group consisting of chronic lymphocytic leukemia, non-Hodgkin' s lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenstrom's macroglobulinemia. In certain embodiments, the cancer is selected from the group consisting of non-Hodgkin's lymphomas (such as diffuse large B-cell lymphoma), acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye,

retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, bone (e.g., metastatic bone), esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS- related (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancers such as cervical carcinoma (human papillomavirus), B-cell lymphoproliferative disease and nasopharyngeal carcinoma (Epstein-Barr virus), Kaposi's sarcoma and primary effusion lymphomas (Kaposi's sarcoma herpesvirus), hepatocellular carcinoma (hepatitis B and hepatitis C viruses), and T-cell leukemias (Human T-cell leukemia virus-1), B cell acute lymphoblastic leukemia, Burkitt's leukemia, juvenile myelomonocytic leukemia, hairy cell leukemia, Hodgkin' s disease, multiple myeloma, mast cell leukemia, and mastocytosis. In selected embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate conditions (e.g., benign prostatic hypertrophy (BPH)). In some embodiments, the hyperproliferative disorder is an inflammatory, immune, or autoimmune disorder. In some embodiments, the hyperproliferative disorder is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcet' s disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn' s disease, lupus, and lupus nephritis. In an embodiment, the method of any of the foregoing embodiments further includes the step of administering an acid reducing agent to the mammal. In an embodiment, the acid reducing agent is selected from the group consisting of proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole; H ₂ receptor antagonists, such as cimetidine, ranitidine, and famotidine; and antacids such as bicarbonates, carbonates, and hydroxides of aluminium, calcium, magnesium, potassium, and sodium.

In some embodiments, the invention provides pharmaceutical compositions of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) described herein for use in the treatment of cancers such as thymus cancer, brain cancer (e.g., glioma), lung cancer, squamous cell cancer, skin cancer (e.g., melanona), eye cancer, retinoblastoma cancer, intraocular melanoma cancer, oral cavity cancer, oropharyngeal cancer, bladder cancer, gastric cancer, stomach cancer, pancreatic cancer, bladder cancer, breast cancer, cervical cancer, head and neck cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, colon cancer, esophageal cancer, testicular cancer, gynecological cancer, ovarian cancer, thyroid cancer, CNS cancer, PNS cancer, AIDS-related cancer (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer, and epidermoid cancer. In some embodiments, the invention provides pharmaceutical compositions of a solid form of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) described herein for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)). In some embodiments, the invention provides

pharmaceutical compositions of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) described herein for use in the treatment of disorders such as myeloproliferative disorders (MPDs), myeloproliferative neoplasms, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), myelodysplastic syndrome, chronic myelogenous leukemia (BCR-ABLl-positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, or mastocytosis. The invention also provides compositions for use in treating a disease related to vasculogenesis or angiogenesis in a mammal which can manifest as tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and hemangioma.

In some embodiments, the invention provides a method of treating a solid tumor cancer with a composition including the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) described herein. In some embodiments, the invention provides a method of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, squamous cell carcinoma including head and neck cancer. In an embodiment, the invention provides a method for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, and colorectal cancer using a combination of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) described herein and a second agent selected from the group consisting of bendamustine, venetoclax, gemcitabine, albumin-bound paclitaxel, rituximab, obinutuzumab, ofatumumab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab. In an embodiment, the invention provides a method for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, and colorectal cancer using a combination of a BTK inhibitor and bendamustine, venetoclax, gemcitabine, albumin-bound paclitaxel, rituximab, obinutuzumab, ofatumumab, pembrolizumab, nivolumab, durvalumab, avelumab, and

atezolizumab, wherein the BTK inhibitor is a solid form of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) described herein.

In some embodiments, the invention relates to a method of treating an inflammatory, immune, or autoimmune disorder in a mammal with a composition including the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) described herein. In selected embodiments, the invention also relates to a method of treating a disease with a composition including the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) described herein, wherein the disease is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcets disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's Disease, lupus, and lupus nephritis.

In some embodiments, the invention relates to a method of treating a hyperproliferative disorder in a mammal with a composition including the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) described herein, wherein the hyperproliferative disorder is a B cell hematological malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin' s lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, myelodysplatic syndromes, or myelofibrosis. In some embodiments, the invention relates to a method of treating a hyperproliferative disorder in a mammal with a composition including the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate) described herein, wherein the hyperproliferative disorder is selected from the group consisting of chronic myelocytic leukemia, acute myeloid leukemia,

DLBCL (including activated B-cell (ABC) and germinal center B-cell (GCB) subtypes), follicle center lymphoma, Hodgkin's disease, multiple myeloma, indolent non-Hodgkin' s lymphoma, and mature B-cell ALL.

In some embodiments, the hyperproliferative disorder is a subtype of CLL. A number of subtypes of CLL have been characterized. CLL is often classified for immunoglobulin heavy- chain variable-region (IgVH) mutational status in leukemic cells. R. N. Damle, et al., Blood 1999, 94, 1840-47; T. J. Hamblin, et al, Blood 1999, 94, 1848-54. Patients with IgV _H mutations generally survive longer than patients without IgVH mutations. ZAP70 expression (positive or negative) is also used to characterize CLL. L. Z. Rassenti, et al, N. Engl. J. Med. 2004, 351, 893-901. The methylation of ZAP-70 at CpG3 is also used to characterize CLL, for example by pyro sequencing. R. Claus, et al, J. Clin. Oncol. 2012, 30, 2483-91; J. A. Woyach, et al., Blood 2014, 123, 1810-17. CLL is also classfied by stage of disease under the Binet or Rai criteria. J. L. Binet, et al., Cancer 1977, 40, 855-64; K. R. Rai, T. Han, Hematol. Oncol. Clin. North Am. 1990, 4, 447-56. Other common mutations, such as l lq deletion, 13q deletion, and 17p deletion can be assessed using well-known techniques such as fluorescence in situ hybridization (FISH). In an embodiment, the invention relates to a method of treating a CLL in a human, wherein the CLL is selected from the group consisting of IgVH mutation negative CLL, ZAP-70 positive CLL, ZAP-70 methylated at CpG3 CLL, CD38 positive CLL, chronic lymphocytic leukemia characterized by a 17pl3.1 (17p) deletion, and CLL characterized by a l lq22.3 (1 lq) deletion.

In some embodiments, the hyperproliferative disorder is a CLL wherein the CLL has undergone a Richter's transformation. Methods of assessing Richter's transformation, which is also known as Richter's syndrome, are described in Jain and O'Brien, Oncology, 2012, 26, 1146-52. Richter's transformation is a subtype of CLL that is observed in 5-10% of patients. It involves the development of aggressive lymphoma from CLL and has a generally poor prognosis.

In some embodiments, the hyperproliferative disorder is a CLL or SLL in a patient, wherein the patient is sensitive to lymphocytosis. In an embodiment, the invention relates to a method of treating CLL or SLL in a patient, wherein the patient exhibits lymphocytosis caused by a disorder selected from the group consisting of a viral infection, a bacterial infection, a protozoal infection, or a post- splenectomy state. In an embodiment, the viral infection in any of the foregoing embodiments is selected from the group consisting of infectious mononucleosis, hepatitis, and cytomegalovirus. In an embodiment, the bacterial infection in any of the foregoing embodiments is selected from the group consisting of pertussis, tuberculosis, and brucellosis.

In some aspects, the invention provides a crystalline solid form of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate), or a pharmaceutical composition comprising said crystalline solid, for use in a method of treating a hyperproliferative disorder in a mammal.

In some aspects, the invention provides a crystalline solid form of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate), or a pharmaceutical composition comprising said crystalline solid form, for use in a method of treating a hyperproliferative disorder in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the crystalline solid form of the particular form of Compound (1) of the invention.

In some aspects, the invention provides the use of a crystalline solid form of the particular form of Compound (1) of the invention (e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate), or a pharmaceutical composition comprising said crystalline solid, in the manufacture or preparation of a medicament for treating a hyperproliferative disorder in a mammal.

In various embodiments of the invention there is provided Compound (I) citrate Form A; pharmaceutical compositions containing it; and, methods of treating disease in a mammal comprising administering to said mammal an effective amount of Compound (I) citrate Form A, or a pharmaceutical composition containing it, suitable diseases being those disclosed herein, such as hyperproliferative diseases like cancer and autoimmune diseases.

In various embodiments of the invention there is provided Compound (I) fumarate Form B; pharmaceutical compositions containing it; and, methods of treating disease in a mammal comprising administering to said mammal an effective amount of Compound (I) fumarate Form B, or a pharmaceutical composition containing it, suitable diseases being those disclosed herein, such as hyperproliferative diseases like cancer and autoimmune diseases.

In particular embodiments of the above aspects, the mammal is a human.

In some embodiments of the above aspects, the hyperproliferative disorder is cancer. In certain embodiments of the above aspects, the cancer is selected from the group consisting of chronic lymphocytic leukemia, non-Hodgkin' s lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenstrom's macroglobulinemia. In certain embodiments of the above aspects, the cancer is selected from the group consisting of non- Hodgkin' s lymphomas (such as diffuse large B-cell lymphoma), acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, bone (e.g., metastatic bone), esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-related (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancers such as cervical carcinoma (human papillomavirus), B-cell lymphoproliferative disease and nasopharyngeal carcinoma (Epstein-Barr virus), Kaposi' s sarcoma and primary effusion lymphomas (Kaposi's sarcoma herpesvirus), hepatocellular carcinoma (hepatitis B and hepatitis C viruses), and T-cell leukemias (Human T-cell leukemia virus-1), B cell acute lymphoblastic leukemia, Burkitt's leukemia, juvenile myelomonocytic leukemia, hairy cell leukemia, Hodgkin' s disease, multiple myeloma, mast cell leukemia, and mastocytosis. In selected embodiments of the above aspects, the method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate conditions (e.g., benign prostatic hypertrophy (BPH)). In some embodiments of the above aspects, the hyperproliferative disorder is an inflammatory, immune, or autoimmune disorder. In some embodiments of the above aspects, the hyperproliferative disorder is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcet' s disease, polymyalgia rheumatica, giant- cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, lupus, and lupus nephritis. In other embodiment of the above aspects, the method of any of the foregoing embodiments further includes the step of administering an acid reducing agent to the mammal. In particular embodiment, the acid reducing agent is selected from the group consisting of proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole; H ₂ receptor antagonists, such as cimetidine, ranitidine, and famotidine; and antacids such as bicarbonates, carbonates, and hydroxides of aluminium, calcium, magnesium, potassium, and sodium.

EXAMPLES

The invention is further illustrated by way of the following examples, which are intended to elaborate several embodiments of the invention. These examples are not intended to, nor are they to be construed to, limit the scope of the invention. It will be clear that the invention may be practiced otherwise than as particularly described herein. Numerous modifications and variations of the present invention are possible in view of the teachings herein and, therefore, are within the scope of the invention.

Methods

Unless indicated otherwise, the following methods were employed.

Ml. X-Ray Powder Diffraction (XRPD) Analysis XRPD analysis was performed using a Bruker D8 or Brucker D4 diffractometer, which is commercially available from Bruker AXS Inc™ (Madison, Wisconsin). The XRPD spectra were obtained by mounting a sample (approximately 10 mg) of the material for analysis on a single silicon crystal wafer mount (e.g., a Bruker silicon zero background X-ray diffraction sample holder) and spreading out the sample into a thin layer with the aid of a microscope slide. The sample was spun at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a copper long-fine focus tube operated at 40 kV and 40 mA with a wavelength of 1.5406 angstroms (i.e., about 1.54 angstroms). The sample was exposed for 1 second per 0.02 degree 2-theta increment (continuous scan mode) over the range 5 degrees to 40 degrees 2-theta in theta-theta mode. The running time was -17 min for D8 and ~3 min for D4.

Persons skilled in the art of X-ray powder diffraction will understand that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non- unitary aspect ratios that may affect analysis of samples. The skilled person will also understand that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence, the diffraction pattern data presented are not to be taken as absolute values.

XRPD 2Θ values may vary with a reasonable range, e.g., in the range ± 0.2° and that XRPD intensities may vary when measured for essentially the same crystalline form for a variety of reasons including, for example, preferred orientation. Principles of XRPD are described in publications, such as, for example, Giacovazzo, C. et al. (1995), Fundamentals of

Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; and Klug, H. P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York.

M2. DSC Analysis

DSC analysis was performed on samples prepared according to standard methods using a Q SERIES™ Q1000 or D2000 DSC calorimeter available from TA INSTRUMENTS® (New Castle, Delaware). A sample (approximately 2 mg) was weighed into an aluminum sample pan and transferred to the DSC. The instrument was purged with nitrogen at 50 mL/min and data collected between 22 °C and 300 °C, using a dynamic heating rate of 10 °C/minute. Thermal data was analyzed using standard software, e.g., Universal V.4.5A from TA INSTRUMENTS®.

M3. Thermogravimetry Analysis (TGA)

TGA was performed on samples prepared according to standard methods using a Q SERIES™ Q5000 thermogravimetry analyzer available from TA Instruments

INSTRUMENTS® (New Castle, Delaware). A sample (approximately 5 mg) was placed into an aluminum sample pan and transferred to the TGA furnace. The instrument was purged with nitrogen at 50 mL/min and data collected between 25°C and 300 °C, using a dynamic heating rate of 10 °C/minute. Thermal data was analyzed using standard software, e.g., Universal V.4.5A from TA INSTRUMENTS®.

Example 1. Compound (I) polymorphic Form A

1.1 Synthesis of Com ound (I).

To a solution of 4-bromo-2-methoxy-benzoic acid (15.3 g, 66.2 mmol) in

dichloromethane (250 mL) was added pyridin-2-amine (6.9 g, 72.8 mmol) and DIPEA (34.6 mL, 198.7 mmol). HATU (32.7 g, 86.1 mmol) was added and the mixture was stirred at room temperature overnight. Water (200 mL) was added and the reaction mixture was stirred for 1 hour. The organic layer was concentrated under reduced pressure. DCM (50 mL) was added and the solution was allowed to crystallize over the weekend. The solids were filtered off, washed twice with diethyl ether (10 mL) and dried under reduced pressure to give 4-bromo-2- methoxy-N-(2-pyridyl)benzamide (14.4 g, 66.8%) as light brown crystals. LC-MS (Method A) Rt: 6.05 min; m/z 307.0 + 309.0 (1: 1) (M+H) ⁺ .

To a solution of 4-bromo-2-methoxy-N-(2-pyridyl)benzamide (14.4 g, 46.9 mmol) in 1,4- dioxane (175 mL) was added bis(pinacolata)diboron (14.3 g, 56.3 mmol) and potassium acetate (9.2 g, 93.8 mmol). PdC12(dppf).DCM (1.9 g, 2.3 mmol) was added and the mixture was stirred at 100 oC for 5 hours. The reaction mixture was diluted with water (150 mL) and extracted twice with ethyl acetate (150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (0 to 50% ethyl acetate in heptane). The fractions containing product were concentrated under reduced pressure. The residue was suspended in heptane (150 mL) and stirred for 30 minutes. The solids were filtered off and washed twice with heptane (15 mL), to give 2- methoxy-N-(2-pyridyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboro lan-2-yl)benzamide (10.4 g, 62.6%) as a white solid. LC-MS (Method A) Rt: 6.86 min; m/z 355.2 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6, 300 K): δ = 10.51 (1H, s), 8.36 (1H, m), 8.26 (1H, d, J = 8.4 Hz), 7.89 (1H, d, J =7.6 Hz), 7.85 (1H, m), 7.41 (1H, dd, Jl = 7.6 Hz, J2 = 0.9 Hz), 7.38 (1H, s), 7.17 (1H, m), 4.01 (3H, s , 1.33 (12H, s).

Preparation of l-Bromo-3-r(2S)-pyrrolidin-2-yllimidazorL5-alpyrazin-8-amine .

A 2000 mL round bottom flask equipped with a magnetical stirrer was charged with 37% hydrogen chloride (660 mL, 7971 mmol). Benzyl (2S)-2-(8-amino-l-bromo-imidazo[l,5- a]pyrazin-3-yl)pyrrolidine-l-carboxylate sulfuric acid (205 g, 399 mmol) was added portion wise (appr. 30 min) and the reaction mixture was stirred for 8 hours at 50 °C. The reaction mixture was allowed to cool to room temperature over 8 h. The reaction mixture was washed with MTBE (3 X 1200 mL). 33% sodium hydroxide in water (-600 mL) was added drop-wise to the aqueous phase until a pH of appr. 14 was reached, while maintaining the temperature at 20-30 °C (MTBE layer appears). After addition, the aqueous phase was stirred for 1 hr, and extracted with dichloromethane (2 X 1500 mL). Activated carbon (10 g) was added to the combined DCM layers and the mixture was stirred for 1 hr at 40 °C. The solids were removed by filtration over dicalite and the filtrate was concentrated under reduced pressure to give l-bromo-3-[(2S)- pyrrolidin-2-yl]imidazo[l,5-a]pyrazin-8-amine (112.3 g, 397.9 mmol, 99.8% yield) as an off- white solid. LC-MS (Method A) Rt: 0.673 min; m/z 282.0 + 284.0 (1: 1) (M+H) ⁺ ; 1H NMR (400 Mhz, DMSO-d6, 300K): δ = 7.72 (1H, d, J = 5.0 Hz), 6.98 (1H, d, J = 5.0 Hz), 4.45 (1H, t , J = 6.9 Hz), 2.99 (1H, br s), 2.77 - 2.90 (2H, m), 2.09 - 2.20 (1H, m), 1.99 - 2.09 (1H, m), 1.78 - 1.89 (1H, m), 1.66 - 1.78 (1H, m).

Preparation of 4-r8-amino-3-r(2S)-pyrrolidin-2-yllimidazorL5-alpyrazin-l-yl l-2-methoxy-N-(2- p yrid yl)b enzamide .

l-Bromo-3-[(2S)-pyrrolidin-2-yl]imidazo[l,5-a]pyrazin-8-amin e (102 g, 361.52 mmol), 2-methoxy-N-(2-pyridyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxabo rolan-2-yl)benzamide (134.46 g, 379.61 mmol) and potassium iodide (18.00 g, 108.46 mmol) were loaded into a three-necked 3L flask. 2-Butanol (500 mL) and water (800 mL) were added and the resulting suspension was stirred while nitrogen gas was bubbled through. Triethyl amine (109.75 mL, 1084.60 mmol) was added, and the suspension slowly dissolved. Bis(tert-butyldicylcohexylphosphine)dichloro palladium(II) (Pd-166, 1.24 g, 1.81 mmol) was added and the reaction mixture was

deoxygenated again during 10 minutes and stirred at 82 °C overnight to give a tan-colored suspension. The reaction mixture was allowed to cool to room temperature. The mixture was then heated to 40 °C and water (1600 mL) was added, and after the addition allowed to cool to room temperature again. The mixture was filtered and the cake was washed with water (250 mL) and heptane (250 mL). The solid was suspended in heptane (500 mL) and co-evaporated. The solid was co-evaporated again with heptane (500 ml) and dried under reduced pressure at 50 °C overnight to give 4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-y l]-2-methoxy-N- (2-pyridyl)benzamide (141 g, 328.31 mmol, 90.8% yield) as a light yellow solid. LC-MS (Method A) Rt: 2.856 min; m/z 430.2 (M+H) ⁺ ; HPLC (Method C) Rt: 3.757 min; purity 98.7%.

Preparation of 4-r8-amino-3-r(2S)-pyrrolidin-2-yllimidazori,5-alpyrazin-l-y ll-2-methoxy-N-(2- p yrid yl)b enzamide .

To a solution of 4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-y l]-2- methoxy-N-(2-pyridyl)benzamide (141.24 g, 324.92 mmol) and but-2-ynoic acid (30.05 g, 357.42 mmol) in DCM (2050 mL) was slowly added triethyl amine (113.22 mL, 812.31 mmol) under a nitrogen atmosphere. To the resulting slurry, a propylphosphonic anhydride solution (50% in DCM, 217.11 g, 341.17 mmol) was added dropwise over ca. 70 minutes (the dropping funnel was rinsed once with 5 mL DCM). The resulting reaction mixture was stirred for 1 hour at room temperature. Another 16.1 g of propylphosphonic anhydride solution (50% in DCM) was added and the reaction mixture was stirred for 30 minutes at room temperature. Then, another 6.9 g of propylphosphonic anhydride solution (50% in DCM) was added to force the reaction to completion, and the reaction mixture was stirred for 30 minutes at room temperature. Water (500 mL) was added the resulting mixture was stirred vigorously for 10 minutes. The layers were separated and the organic layer was washed twice with water (700 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure in a 3L roundbottom flask to give crude 4-[8-amino-3-[(2S)-l-but-2-ynoylpyrrolidin-2-yl]imidazo[l,5- a]pyrazin-l-yl]-2- methoxy-N-(2-pyridyl)benzamide (169 g, 341.05 mmol, quantitative yield) as a yellow foam. The flask containing the foam was heated to 90°C in an oil bath. Hot ethanol (100%, 80 °C, 720 mL) was added all at once and the flask was agitated until the foam was dissolved completely. A magnetic stirring bar was added, and the flask was placed in a water bath of 60°C. Heating of this bath was then switched off and under continuous stirring, the product crystallized while slowly cooling down to room temperature overnight. Three additional batches of crude 4-[8-amino-3- [(2S)-l-but-2-ynoylpyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-y l]-2-methoxy-N-(2- pyridyl)b enzamide (145 g, 150 g and 180 g, respectively) were prepared as above and

crystallized following the same procedure. The resulting crystallized suspensions were pooled together in a 5L Erlenmeyer, mixed, collected on a filter and washed with ethanol (1 L). The solids were dried under reduced pressure at 50°C for 17 hours and 24 hours at room temperature until no weight decrease was observed to give (S)-4-(8-amino-3-(l-but-2-ynoylpyrrolidin-2- yl)imidazo[l,5-a]pyrazin-l-yl)-2-methoxy-N-(pyridin-2-yl)ben zamide (495.35 g, 1014.7 mmol, 76.04% yield) as a pale yellow solid. LC-MS (Method A) Rt: 4.147 min; m/z 496.1 (M+H) ⁺ ; HPLC (Method B) Rt: 5.275 min; purity 99.7%; 1H NMR (400 Mhz, DMSO-d6, 300K): δ = 10.49 (1H, s), 8.37 (1H, m), 8.30 (1H, d, J = 8.3 Hz), 8.04 (1H, dd, Jl = 2.1 Hz, J2 = 7.8 Hz), 7.87 (1H, dt, Jl = 1.9 Hz, J2 = 7.8 Hz), 7.79 (1H, d, J = 5.0 Hz), 7.44 - 7.36 (2H, m), 7.20 - 7.11 (2H, m), 6.20 (2H, d, J = 27.7 Hz), 5.76 - 5.45 (1H, m), 4.07 (3H, d, J = 2.4 Hz), 3.83 (1H, t, J = 6.8 Hz), 3.69 - 3.38 (1H, m), 2.45 - 1.92 (4H, m), 2.01 (2H, s), 1.65 (1H, s).

1.2 Analytical Methods

The following liquid chromatography (LC) and mass spectrometry (MS) methods may be used to characterize compounds included in the present invention.

Method A

LC-MS spectrometer (Agilent)

Detector: DAD (210, 254 and 280 nm)

Mass detector: API-ES (10-2000 amu, pos./neg. ion mode)

Eluents (mobile phase): A: 0.1% formic acid in MilliQ-water, B: acetonitrile

Column: Waters XTerra C18 MS, 50x4.6 mm ID, 2.5 μιη

Flow rate: 0.5 mL/min

Gradient elution program:

Time (min) A ( %) B (%)

0.0 90 10

7.0 10 90

7.1 0 100

10.0 90 10

Method B:

HPLC: Gilson analytical HPLC system

Column: Phenomenex Luna CI 8(2) (100 x 2.00 mm, 5 μιη)

Detector: UV/Vis (210/240 nm)

Flow rate: 1 mL/min

Eluents (mobile phase): A: acetonitrile, B: acetonitrile / MilliQ-water in MilliQ-water.

Gradient elution program:

Time (min) A (%) B (%) C (%)

0.00 0 97 3

11.90 97 0 3

14.40 97 0 3

15.40 0 97 3

Method C:

HPLC: Gilson analytical HPLC system

Column: Phenomenex Luna CI 8(2) (100 x 2.00 mm, 5 μιη)

Detector: UV/Vis (210/240 nm)

Flow rate: 1 mL/min

Eluents (mobile phase): A: acetonitrile, B: acetonitrile / MilliQ-water = 1/9 (v/v), C: 0,1% TFA in MilliQ-water.

Gradient elution program:

Time (min) A (%) B (%) C (%)

0.00 0 97 3

2.80 0 97 3

14.70 97 0 3

17.20 97 0 3

18.20 0 97 3

Sample injection at 2.80 min 1.2. X-Ray Powder Diffraction

The material was analyzed by XRPD using method Ml.

XRPD analysis showed the material was crystalline.

FIG. 1 shows the XRPD pattern for Compound (I) free base (Form A) measured using reflectionlgeometry. The most abundant or discriminatory peaks are identified in Table 1. Angle 2-Theta (2Θ) Intensity (%)

10.0 100.0

24.0 53.7

25.9 47.3

14.6 43.1

16.9 36.6

20.0 33.7

13.9 24.0

6.2 22.6

12.3 18.3

7.9 4.4

Table 1. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) free base Form A

Three characteristic peaks are found at about 2-theta = 7.9, 10.0 ° and 14.6°. Thus, Compound (I) free base Form A is characterised in providing at least one of the following 2Θ values measured using CuKa radiation: 7.9°, 10.0° and 14.6°, plus or minus 0.2 °2-theta.

Single crystals of Form A were obtained from slow evaporation of an acetonitrile/heptane solution. Single crystal structure analysis confirmed that Form A is an anhydrous form.

Crystallographic data: Space group triclinic PI, unit cell dimensions: a = 7.606(1) A, b =

11.509(2) A, c = 14.456(2) A, = 89.486(4)°, β= 85.898(5)°, γ= 77.268(5)°, V= 1231.2(4) A ³ .

1.3 DSC and TGA

Form A was analyzed by thermal techniques. DSC analysis (using method M2) indicated that Form A has an endotherm event of melting/decomposition with an onset at 232 °C and a peak at 235 °C, followed by an exotherm event. TGA (using method M3) indicated that Form A exhibits a mass loss of about 0.7 % upon heating from about 25 °C to about 150 °C, indicating that it is anhydrous form. A representative DSC/TGA thermogram of Form A is shown in Figure 2.

These data indicate that Form A is anhydrous, non-hygroscopic and has high crystallinity. No form change was observed after storage at ambient temperature and high temperature (50°) and therefore, the anhydrous Form A is stable and not likely to change form with time.

Example 2. Compound (I) polymorph Form B

2.1 Synthesis.

144 mg (0.3 mmol) of Compound (I) free base Form A (from Example 1) was dissolved in 1.2 ml of 0.5 N HC1 aqueous solution (0.6 mmol) to get a clear solution. 1.2 ml of 0.5 N NaOH aqueous solution was added to the solution slowly; a light yellow gel was formed. The gel was stirred at ambient conditions for 3 days and an off-white solid was obtained. The solid was filtered and air dried.

2.2 XRPD analysis.

X-ray powder diffraction analysis (using method Ml) identified a new polymorph (Form

B).

FIG. 3 shows the XRPD pattern for Compound (I) free base (Form B) measured using reflectionlgeometry. The most abundant or discriminatory peaks are identified in Table 2.

Table 2. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) polymorph Form B.

Three characteristic peaks are found at about 2-theta = 10.8 ⁰ and 12.6°. Thus, Compound (I) free base Form B is characterised in providing at least one of the following 2Θ values measured using CuKa radiation: 10.8° and 12.6°, plus or minus 0.2 °2-theta.

2.3 DSC and TGA.

Form B was analyzed by thermal techniques using M2. DSC analysis indicated that Form B has an endotherm event of desolvation with an onset at 36 °C and a peak at 73 °C. Additional exotherm event with an onset at 166 °C and a peak at 176 °C and endotherm event with an onset at 209 °C and a peak at 222 °C are also identified. TGA (using method M3) indicated that Form B exhibits a mass loss of about 5.5 % upon heating from about 25 °C to about 100 °C.

Theoretical sesqui hydrate would be expected to contain -5.2% solvent, indicating that this form is hydrated. A representative DSC/TGA thermogram of Form B is shown in Figure 4.

Compound (I) free base Form B shows poor thermal stability and starts to lose crystallinity at the low temperature. It also appears to be highly hygroscopic, losing crystallinity as moisture is absorbed. Example 3. Compound (I) Salt Screening

A salt screening of Compound (I) was carried out as follows:

Equimolar amounts of amorphous Compound (I) free base prepared according to Example 1 and counter-ions were added to a glass 96 well plate, lOOuL of each component. The plates were then sealed, pin-holed and allowed to slowly crystallise prior to analysis by polarised light microscopy to look for the presence of crystalline material. The following counter-ions were screened:

1. Acetic acid l-hydroxy-2-napthoic acid

2. Adipie acid 24. 2-furoic acid

3. Benzene Sul phonic acid 25. Ascorbic Benzoic acid 26. Gentisic (2,5 dihydroxy benzoic acid) c, Ci.rma.mic ac d 27. Glutaric

6. Citric acid 28. Glucuronic

"7 DL Lactic acid 29. Glycolic

8. Ethane DisupLhonie acid 30. Hippuric

9. Ethane sulphonic acid 31. Ketoglutaric

10. Fumaric acid 32. Mandelic

11. Hydrochloric acid 33. Oxalic

12. Methane sulphonic acid 34. Propioic

13. NapadisyUc acid L-pyro glutamic acid

14, Phosplioxic acid 36. Vanillic

15. L-Tartaric acid 37. Camphoric

16, Maleic acid 38. 2,4,6 trimethylbenzenesulfonic

17. Malic acid (mesitylene sulfonic acid)

18. Maloiiic acid 39. Glutamic

19. Sacc arin

20, Succinic acid

21. Sulphuri acid

22 Toluene sulphonic acid

Table 3 - list of counter ions used in Compound (I) salt screen.

Crystalline hits were obtained from the majority of counter-ions screened (although for some counter-ions hits were only obtained from aqueous co-solvents, suggesting hydrate formation for these particular prospective salts).

Initial salt scale-up was performed by adding equimolar amounts of free base and counter-ion in acetonitrile and allowing to evaporate slowly over several hours. The following counter-ions were used: Methanesulfonic, benzenesulfonic, ethanesulfonic, toluenesulfonic, malic, glutamic, gentisic, mesitylene sulfonic acid, HCl, p-Xylene-2-sulfonic acid, adipic, malonic, benzoic, trans-cinnamic acid. Highly crystalline salts were obtained for malonic acid (Example 4) and mesitylene sulfonic acid (Examples 5-7). With the other counterions, amorphous glasses were obtained. Example 4. Preparation of Compound (I) mesitylene sulphonic acid salt

4.1 Synthesis.

lOOOmg of Compound (I) free base prepared according to Example 1, was dissolved in 150ml of acetonitrile and heated to ensure complete dissolution. 1.1 molar equivalents of 2- Mesitylene sulphonic acid dihydrate (520mg) was dissolved in acetonitrile. The counterion solution was added to the Compound (I) free base solution. No precipitation occurred. The resulting solution was allowed to evaporate to less than 75ml. This solution was then left to stir overnight. Precipitation had occurred upon stirring. The material was filtered.

4.2. Physical Characterization of Crystalline Compound (I) mesitylene sulphonic acid salt 4.2.1 X-Ray Powder Diffraction using a Bruker D4 Analytical Instrument.

The X-ray powder diffractogram of the Compound (I) mesitylene sulphonic acid salt was determined by mounting a sample of the crystalline material on a Bruker single silicon crystal (SSC) wafer mount and spreading out the sample into a thin layer with the aid of a microscope slide. The sample was spun at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a copper long-fine focus tube operated at 40kV and 40mA with a wavelength of 1.5418 angstroms. The collimated X-ray source was passed through an automatic variable divergence slit set at V20 and the reflected radiation directed through a 5.89mm anti scatter slit and a 9.55mm detector slit. Samples were measured in reflection geometry in θ - 2Θ configuration over the scan range 2° to 40° 2Θ with a nominal 0.12 second exposure per 0.02° increment. The instrument was equipped with a Position sensitive detector (Lynx eye).

XRPD analysis showed the material was crystalline. FIG. 5 shows the XRPD pattern for Compound (I) mesitylene sulphonic acid salt (Form

A) measured using reflection| geometry. The most abundant or discriminatory peaks are identified in Table 4.

Table 4. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) mesitylene sulphonic acid salt.

Two characteristic peaks are found at about 2-theta = 21.9° and 7.3°. Thus, Compound (I) Mesitylene sulphonic acid salt (Form A) is characterised in providing at least one of the following 2Θ values measured using CuKa radiation: 21.9° and 7.3°, plus or minus 0.2 °2-theta. 4.2.2 Differential Scanning Calorimetry (DSC)

DSC was carried out with a TA Instruments Q2000 instrument. Typically less than 5mg of material contained in a standard aluminium pan fitted with a lid was heated over the temperature range 25°C to 300°C at a constant heating rate of 10°C per minute. A purge gas using nitrogen was used - flow rate 50ml per minute.

DSC analysis of Compound (I) mesitylene sulphonic acid salt (Form A) from Example 4.1, shows an initial event with an onset at 76.3°C and a peak at 108.9°C followed by a subsequent melting endotherm with an with an onset of 229.9°C and a peak at 234.1° C (Fig. 6). 4.2.3 NMR analysis

The stoichiometry was confirmed using nuclear magnetic resonance (NMR)

spectroscopy. Compound (I) mesitylene sulphonic acid salt (Form A) sample from Example 2.1 was dissolved in DMSO and a proton nuclear magnetic resonance spectra was determined at 27°C using a Bruker Avance 400 (400MHz) spectrometer.

NMR analysis showed that the material from Example 2.1 had a stoichiometry of 1: 1.

Example 5. Preparation of Compound (I) malonate Form A

5.1 Synthesis.

248 mg (0.5 mmol) of Compound (I) free base Form A (from Example 1) was dissolved in 5.0 ml of DCM (dichloromethane) to get a clear solution. 52 mg of (0.5 mmol) of malonic acid was dissolved in 0.5 ml of MeOH and 0.5 ml of DCM. The two solutions were mixed and the resulting yellow solution was evaporated in the ambient condition. A yellowish gel-like material was obtained. 1.0 ml of MTBE was added to the light yellow semi-solid, and the slurry was stirred at the ambient condition for 1 days, and a off-white solid was obtained. The resulting off-white solid was dried in air. Polarized light microscope shows that the solid is an amorphous material.

10 mg of amorphous solid of Compound (I) malonate was dissolved in 0.2 ml of water. The resulting solution was stirred at the ambient condition for 10 minutes resulting in precipitate formation. The resulting slurry was stirred at the ambient conditions for 3 days.

5.2. Physical Characterization of Crystalline Form A of Compound (I) Malonate 5.2.1 X-Ray Powder Diffraction

The slurry from Example 5.1 was placed in an XRPD sample holder and measured as the wet cake in accordance with method Ml.

XRPD showed that a crystalline material was obtained.

FIG. 7 shows the XRPD pattern for Compound (I) malonate salt (Form A) measured using reflection! geometry. The most abundant or discriminatory peaks are identified in Table 5. Angle 2-Theta (2Θ) Intensity (%)

6.9 100.0

14.0 3.2

15.8 3.0

14.7 2.7

14.4 2.7

10.9 2.4

7.3 2.3

5.5 2.0

12.4 1.8

7.7 1.6

Table 5. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) malonate salt (Form A). Three characteristic peaks are found at about 2-theta = 6.9°, 10.9° and 12.4°. Thus,

Compound (I) malonate salt (Form A) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 6.9°, 10.9° and 12.4°, plus or minus 0.2 °2-theta.

After drying, Compound (I) malonate Form A was found to convert to Form B demonstrating that Compound (I) malonate Form A is not particularly stable.

Example 6: Preparation of Compound (I) malonate Form B

6.1 Synthesis.

496 mg (1.0 mmol) of Compound (I) was dissolved in 10.0 ml of DCM

(dichloromethane) to get a clear solution. 104 mg of (1.0 mmol) of malonic acid was dissolved in 1.0 ml of DCM and 1.0 ml of MeOH. The two solutions were mixed and stirred at ambient temperature for 1 hour. The resulting yellow solution was evaporated in GeneVac. The yellowish semi-solid material was dissolved in 1.0 ml of acetone. 2.0 ml of H ₂ 0 was added and an off- white solid started to precipitate. An additional 2.0 ml of H ₂ 0 was added and stirred for 1 hour. The resulting slurry was evaporated at ambient condition overnight to a volume of ~4 ml with more crystalline materials precipitated on the wall of the vial. The mother liquor was moved to another vial. The mother liquors were combined and condensed to ~2ml, more solid was precipitated out. Solid material was then collected by filtration. The solid materials were combined and dried in air to yield 160 mg of off white solid.

6.2. Physical Characterization of Crystalline Form B of Compound (I) Malonate

6.2.1 X-Ray Powder Diffraction

The material from Example 4.1 was placed in an XRPD sample holder and measured in accordance with method Ml.

XRPD showed that a crystalline material was obtained which is a distinct malonate form (Form B) from that in Example 5.

FIG. 8 shows the XRPD pattern for Compound (I) malonate salt (Form B) measured using reflectionl geometry. The most abundant or discriminatory peaks are identified in Table 6.

Table 6. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) malonate salt (Form B).

Three characteristic peaks are found at about 2-theta = 8.7°, 9.4° and 13.6°. Thus, Compound (I) malonate salt (Form B) is characterized in providing at least one of the following 2-theta values measured using CuKa radiation: 8.7°, 9.4° and 13.6°, plus or minus 0.2 °2Θ.

6.2.2 DSC and TGA

Compound (I) malonate Form B was analyzed by thermal techniques using method M2. DSC analysis indicated that Form B has an endotherm event of desolvation with an onset at 34 °C and a peak at 74 °C. Additional endotherm event of melting/decomposition with an onset at 131 °C and a peak at 139 °C is also identified. TGA (using method M3) indicated that Form B exhibits a mass loss of about 9.5 % upon heating from about 25 °C to about 100 °C. A

representative DSC/TGA thermogram of Compound (I) malonate Form B is shown in Figure 9.

Example 7: Preparation of Compound (I) malonate Form C

7.1 Synthesis.

10 mg of amorphous solid of Compound (I) malonate from Example 3 was dissolved in a mixture of 0.1 ml of water and 0.1 ml of MeOH (or acetone, or ACN). The resulting solution was evaporated at ambient conditions for 1 day. The resulting solid was filtered and dried in air.

7.2. Physical Characterization of Crystalline Form C of Compound (I) Malonate

7.2.1 X-Ray Powder Diffraction

The material from Example 5.1 was placed in an XRPD sample holder and measured in accordance with method Ml.

XRPD shows that a distinct crystalline material (Form C) was obtained.

FIG. 10 shows the XRPD pattern for Compound (I) malonate salt (Form C) measured using reflection! geometry. The most abundant or discriminatory peaks are identified in Table 7.

Angle 2-Theta (2Θ) Intensity (%)

8.3 100.0

8.6 5.4

13.0 4.8

5.4 3.0

16.3 2.6

16.6 2.4

8.9 2.3

15.1 2.1

21.2 1.5

9.3 1.4

Table 7. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) malonate salt (Form C).

Three characteristic peaks are found at about 2-theta = 5.4, 8.3 and 13.0°. Thus, Compound (I) malonate salt (Form C) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 5.4, 8.3 and 13.0°, plus or minus 0.2 °2-theta. 7.2.2 DSC and TGA

Compound (I) malonate Form C was analyzed by thermal techniques using method M2. DSC analysis indicated that Form C has an endotherm event of desolvation with an onset at 39 °C and a peak at 76 °C. Additional endotherm event of melting/decomposition with an onset at 110 °C and a peak at 114 °C is also identified. TGA (using method M3) indicated that Form C exhibits a mass loss of about 5.2 % upon heating from about 25 °C to about 100 °C. A representative DSC/TGA thermogram of Form C is shown in Figure 11. Example 8: Preparation of Compound (I) citrate Form A

8.1 Synthesis.

Approximately 6g amorphous Compound (I) prepared according to Example 99 of WO2013/010868 was dispensed in an automated 250 mL reactor. 60 mL acetone(95%)- water(5%) was added while stirring with a stir rate of 400 rpm. The mixture was heated to 40°C and Compound (I) dissolved. A 1: 1 ratio citric acid (2.32 g) was added. The mixture was stirred for 30 min at 40°C. During this time period some solids appeared. Some extra solvent (40 mL) was added and the solids dissolved again. A few minutes after dissolving; crystallization started again. The mixture was allowed to stir for another hour. The mixture was then cooled to 10°C (rate: 0.1°C/min) and stirred for 16 hours. The solids were filtered and dried using a vacuum oven. The yield of the experiment was ±94%.

8.2. Physical Characterization of Crystalline Compound (I) Citrate Form A

8.2.1 X-Ray Powder Diffraction

The material from Example 8.1 was placed in an XRPD sample holder and measured in accordance with method Ml.

XRPD shows that a distinct crystalline material (Form A) was obtained.

FIG. 12 shows the XRPD pattern for Compound (I) citrate salt (Form A) measured using reflection! geometry. The most abundant or discriminatory peaks are identified in Table 8.

Angle 2-Theta (2Θ) Intensity (%)

9.7 100.0

6.7 95.3

21.5 69.6

18.9 51.1

15.4 51.0

15.7 43.2

12.7 42.8

10.8 42.7 11.9 38.3

7.2 19.6

Table 8. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) citrate salt (Form A).

Three characteristic peaks are found at about 2-theta = 7.2°, 9.7° and 11.9°. Thus, Compound (I) citrate salt (Form A) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 7.2°, 9.7° and 11.9°, plus or minus 0.2 °2-theta.

In various embodiments of the invention there is provided Compound (I) citrate Form A; pharmaceutical compositions containing it; and, methods of treating disease in a mammal comprising administering to said mammal an effective amount of Compound (I) citrate Form A, or a pharmaceutical composition containing it, suitable diseases being those disclosed herein, such as hyperproliferative diseases like cancer and autoimmune diseases.

8.2.2 DSC and TGA.

Form A was analyzed by thermal techniques using method M2. DSC analysis indicated that Form A has a broad endotherm event of desolvation with an onset at 28°C and a peak at

54°C. Additional endotherm event of melting/decomposition with an onset at 134°C and a peak at 144°C is also identified. TGA (using method M3) indicated that Form A exhibits a mass loss of about 1.4 % upon heating from about 25°C to about 120°C. A representative DSC/TGA thermogram of Form A is shown in Figure 13.

Example 9. Preparation of Compound (I) citrate Form B

9.1 Synthesis.

20 mg of Compound (I) citrate Form A (from Example 8) was slurried in 200 ul of H ₂ 0 for 3 days and then evaporated in the ambient condition. The resulting solid was air dried.

9.2. Physical Characterization of Crystalline Compound (I) citrate Form B

9.2.1 X-Ray Powder Diffraction

The material from Example 9.1 was placed in an XRPD sample holder and measured in accordance with method Ml .

XRPD shows that a crystalline material (Form A) was obtained.

FIG. 14 shows the XRPD pattern for Compound (I) citrate salt (Form A) measured using reflection! geometry. The most abundant or discriminatory peaks are identified in Table 9.

Table 9. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) citrate salt (Form B).

Three characteristic peaks are found at about 2-theta = 6.9° and 13.7° and 22.8°. Thus, Compound (I) citrate salt (Form B) is characterized in providing the following 2Θ values measured using CuKa radiation: 6.9°, 13.7° and 22.8°, plus or minus 0.2 °2-theta.

9.2.2 DSC and TGA.

Form B was analyzed by thermal techniques using method M2. DSC analysis indicated that Form B has a broad endotherm event of desolvation with an onset at 68°C and a peak at 88°C. Additional endotherm event of melting/decomposition with an onset at 136 °C and a peak at 143°C is also identified. TGA (using method M3) indicated that Form B exhibits a mass loss of about 7.4 % upon heating from about 25°C to about 100°C. A representative DSC/TGA thermogram of Form B is shown in Figure 15.

Example 10. Preparation of Compound (I) tartrate Form A

10.1 Synthesis.

Approximately 6g amorphous Compound (I) prepared according to Example 99 of

WO2013/010868 was dispensed in an automated 250 mL reactor. 60 mL acetone (95%)-water (5%) was added at a stir rate of 400 rpm. The mixture was heated to 40°C to dissolve the compound. Then a 1: 1 ratio L-tartaric acid (1.83 g) was added. The mixture stirred for 30 min at 40°C. Some solids started to appear. The temperature was dropped to 25°C (0.5 °C/min). Once the mixture had cooled, the anti-solvent dibutyl ether was added dropwise. The first 10% (6 mL) was added at a rate of 0.033 mL/min and the remaining 90% (54 mL) was added at a rate of 0.1 mL/min. The mixture was stirred for an additional 7 hours. The next morning the temperature was dropped to 10°C at a rate of l°C/min. The mixture was stirred for an additional hour. The formed solids were filtered and dried using a vacuum oven. The yield of the experiment was ± 90%.

10.2. Physical Characterization of Crystalline Compound (I) tartrate Form A

10.2.1 X-Ray Powder Diffraction

The material from Example 10.1 was placed in an XRPD sample holder and measured in accordance with method Ml.

XRPD shows that a crystalline material (Form A) was obtained.

FIG. 16 shows the XRPD pattern for Compound (I) tartrate salt (Form A) measured using reflection! geometry. The most abundant or discriminatory peaks are identified in Table 10.

Angle 2-Theta (2Θ) Intensity (%)

6.5 100.0

12.2 61.5

24.5 61.3

11.0 49.8 22.1 40.8

27.1 40.7

18.3 39.9

13.5 39.7

16.1 35.3

8.0 21.4

Table 10. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) tartrate salt (Form A).

Two characteristic peaks are found at about 2-theta = 8.0° and 11.0°. Thus, Compound (I) tartrate salt (Form A) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 8.0° and 11.0°, plus or minus 0.2 °2-theta.

10.2.2 DSC and TGA.

Form A was analyzed by thermal techniques using method M2. DSC analysis indicated that Form A has a broad endotherm event of desolvation with an onset at 59°C and a peak at 97°C. Additional endotherm event of melting with an onset at 156°C and a peak at 172°C is also identified. Method M3 indicated that Form A exhibits a mass loss of about 7.9 % upon heating from about 25°C to about 100°C. A representative DSC/TGA thermogram of Form A is shown in Figure 17.

Example 11. Preparation of Compound (I) tartrate Form B

11.1 Synthesis.

10 mg of Compound (I) tartrate Form A (from Example 10 above) placed in a sample pan of TA Instrument Q5000 GVS (gravity vapor sorption) instrument. The humidity environment of the sample was increased from 40% RH to 90% RH at 25°C, then the humidity of the sample was decreased from 90% RH to 0% RH.

11.2. Physical Characterization of Crystalline Compound (I) tartrate Form B

11.2.1 X-Ray Powder Diffraction The material from Example 11.1 was placed in an XRPD sample holder and measured in accordance with method Ml.

XRPD shows that after completing the GVS study a distinct crystalline form (Form B) was obtained.

FIG. 18 shows the XRPD pattern for Compound (I) tartrate salt (Form B) measured using reflectionl geometry. The most abundant or discriminatory peaks are identified in Table 11.

Table 11. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) tartrate salt (Form B).

Two characteristic peaks are found at about 2-theta = 7.6° and 15.2°. Thus, Compound (I) tartrate salt (Form B) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 7.6° and 15.2°, plus or minus 0.2 °2-theta.

Example 12. Preparation of Compound (I) tartrate Form C

12.1 Synthesis.

5 mg of Compound (I) tartrate Form A was place on a DSC pan. The sample was heated from 22°C to 120°C at a rate of 10°C/minute, then hold then temperature for 10 minutes, followed by cooling down to the ambient temperature at a rate of 10 °C/minute. 12.2. Physical Characterization of Crystalline Compound (I) tartrate Form C

12.2.1 X-Ray Powder Diffraction

The material from Example 12.1 was placed in an XRPD sample holder and measured in accordance with method Ml. The analysis showed that a new crystalline salt form (Form C) was formed.

FIG. 19 shows the XRPD pattern for Compound (I) tartrate salt (Form C) measured using reflection! geometry. The most abundant or discriminatory peaks are identified in Table 12.

Table 12. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) tartrate salt (Form C).

Three characteristic peaks are found at about 2-theta = 17.1°, 25.9° and 26.8°. Thus, Compound (I) tartrate salt (Form C) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 17.1°, 25.9° and 26.8°, plus or minus 0.2 °2-theta.

Example 13. Preparation of Compound (I) fumarate Form A

13.1 Synthesis.

Approximately 6g amorphous Compound (I) prepared according to Example 99 of WO2013/010868 was dispensed in an automated 250 mL reactor. 60 mL THF-water (5%) was added at a stir rate of 400 rpm. The mixture was heated to 50°C to dissolve the compound. A 1 : 1 ratio fumaric acid (1.42 g) was then added. The mixture was slurried for 16 hours at 50°C. The slurry showed a whiter color. The reactor was cooled to 25°C (0.5 °C/min) and stirred for an additional hour. The solids were filtered and dried using a vacuum oven. The yield of the experiment was ± 69%. The lower yield was a direct result of a clogged filter.

13.2. Physical Characterization of Crystalline Compound (I) fumarate Form A

13.2.1 X-Ray Powder Diffraction

The material from Example 13.1 was placed in an XRPD sample holder and measured in accordance with method Ml .

XRPD shows that a crystalline material (Form A) was obtained.

FIG. 20 shows the XRPD pattern for Compound (I) fumarate salt (Form A) measured using reflectionl geometry. The most abundant or discriminatory peaks are identified in Table 13.

Table 13. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) fumarate salt (Form A).

Three characteristic peaks are found at about 2-theta = 12.4°, 13.3° and 23.4°. Thus, Compound (I) fumarate salt (Form A) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 12.4°, 13.3° and 23.4°plus or minus 0.2 °2-theta.

13.2.2 DSC and TGA

Form A was analyzed by thermal techniques using method M2. DSC analysis indicated that Form A has a broad endotherm event of desolvation with an onset at 29°C and a peak at 62°C. Additional endotherm event with an onset at 144°C and a peak at 152°C and endotherm event with an onset at 172°C and a peak at 184°C are also identified. TGA (using method M3) indicated that Form A exhibits a mass loss of about 3.2 % upon heating from about 25°C to about 100°C. A representative DSC/TGA thermogram of Form A is shown in Figure 21.

Example 14. Preparation of Compound (I) fumarate Form B

14.1 Synthesis.

15 mg of Compound (I) fumarate Form A from Example 13 above was suspended in 200 ul of MeOH solvent (or EtOAC, or Acetone, or ACN), the slurry was stirred at the ambient temperature for 3 days.

14.2. Physical Characterization of Crystalline Compound (I) fumarate Form B

14.2.1 X-Ray Powder Diffraction

The material from Example 14.1 was placed in an XRPD sample holder and measured in accordance with method Ml.

XRPD shows that a distinct form (Form B) demonstrating more crystallity was obtained.

FIG. 22 shows the XRPD pattern for Compound (I) fumarate salt (Form B) measured using reflectionl geometry. The most abundant or discriminatory peaks are identified in Table 14.

Angle 2-Theta (2Θ) Intensity (%)

10.0 100.0

25.4 95.6

11.7 80.9

26.0 79.4

8.9 71.6 24.0 71.4

18.3 68.1

14.7 67.3

20.1 42.1

6.2 40.7

Table 14. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) fumarate salt (Form B).

Three characteristic peaks are found at about 2-theta = 6.2°, 10.0°, and 20.1°. Thus, Compound (I) fumarate salt (Form B) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 6.2°, 10.0°, and 20.1°, plus or minus 0.2 °2-theta.

14.2.2 DSC and TGA

Form B was analyzed by thermal techniques using method M2. DSC analysis indicated that Form B has a broad endotherm event of desolvation with an onset at 18°C and a peak at 57°C. Additional endotherm event of melting/decomposition with an onset at 181°C and a peak at 186°C is also identified. TGA (using method M3) indicated that Form B exhibits a mass loss of about 2.1 % upon heating from about 25°C to about 100 °C. A representative DSC/TGA thermogram of Form A is shown in Figure 23.

In various embodiments of the invention there is provided Compound (I) fumarate Form B; pharmaceutical compositions containing it; and, methods of treating disease in a mammal comprising administering to said mammal an effective amount of Compound (I) fumarate Form B, or a pharmaceutical composition containing it, suitable diseases being those disclosed herein, such as hyperproliferative diseases like cancer and autoimmune diseases.

Example 15. Preparation of Compound (I) fumarate Form C

15.1 Synthesis.

5 mg of Compound (I) fumarate Form A was place on a DSC pan. The sample was heated from 22 °C to 120 °C at a rate of 10 °C/minute, then hold then temperature for 10 minutes, followed by cooling down to the ambient temperature at a rate of 10 °C/minute. The result solid was characterized by PXRD and shows that Form C was obtained.

15.2. Physical Characterization of Crystalline Compound (I) fumarate Form C

15.2.1 X-Ray Powder Diffraction

The material from Example 15.1 was placed in an XRPD sample holder and measured in accordance with method Ml .

XRPD shows that a distinct form (Form C) was obtained.

FIG. 24 shows the XRPD pattern for Compound (I) fumarate salt (Form C) measured using reflectionl geometry. The most abundant or discriminatory peaks are identified in Table 15.

Table 15. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) fumarate salt (Form C).

Three characteristic peaks are found at about 2-theta = 6.5°, 8.1°, and 12.2°. Thus, Compound (I) fumarate salt (Form C) is characterized in providing at least one of the following 2-theta values measured using CuKa radiation: 6.5°, 8.1°, and 12.2°, plus or minus 0.2 °2Θ. Example 16. Preparation of Compound (I) Malate Form A

16.1 Synthesis.

Approximately 6g amorphous Compound (I) prepared according to Example 99 of WO2013/010868 was dispensed in an automated 250 mL reactor. 60 mL THF (95%)-water (5%) was added at a stir rate of 400 rpm. The mixture was heated to 40°C to dissolve the material. A 1: 1 ratio L-malic acid (1.63 g) was added. The mixture was stirred for 30 min at 40°C. The temperature was dropped to 25°C (0.5 °C/min). Once the mixture had cooled, the anti-solvent dibutyl ether was added dropwise. The first 10% (6 mL) was added at a rate of 0.033 mL/min and the remaining 90% (54 mL) was added at a rate of 0.1 mL/min. The mixture was stirred for an additional 7 hours. The next morning the temperature was dropped to 10°C at a rate of l°C/min and stirred for an additional hour. The formed solid was filtered and dried using a vacuum oven. The yield of the experiment was ± 91%.

16.2. Physical Characterization of Crystalline Compound (I) malate Form A

16.2.1 X-Ray Powder Diffraction

The material from Example 16.1 was placed in an XRPD sample holder and measured in accordance with method Ml.

XRPD shows that a crystalline material (Form A) was obtained.

FIG. 25 shows the XRPD pattern for Compound (I) malate salt (Form A) measured using reflection! geometry. The most abundant or discriminatory peaks are identified in Table 16.

Angle 2-Theta (2Θ) Intensity (%)

26.2 100.0

23.7 83.2

7.7 78.9

15.6 66.4

27.2 66.0

24.5 64.8

22.1 58.7

16.3 49.5 21.2 48.7

5.2 46.0

Table 16. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) malate salt (Form A).

Two characteristic peaks are found at about 2-theta = 5.2° and 26.2°. Thus, Compound (I) malate salt (Form A) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 5.2°and 26.2°, plus or minus 0.2 °2-theta.

16.2.2 DSC and TGA

Form A was analyzed by thermal techniques using method M2. DSC analysis indicated that Form A has a broad endotherm event of desolvation with an onset at 40°C and a peak at 80°C. Additional endotherm event with an onset at 114°C and a peak at 119°C is also identified. TGA (using method M3) indicated that Form A exhibits a mass loss of about 5.2 % upon heating from about 25 °C to about 100 °C. A representative DSC/TGA thermogram of Form A is shown in Figure 26.

Example 17. Preparation of Compound (I) Malate Form B

17.1 Synthesis.

15 mg of Compound (I) malate Form A (from Example 16) was suspended in 200 ul of H ₂ 0, the slurry was stirred at ambient temperature for 3 days. The slurry was evaporated in ambient conditions to yield an off-white solid.

17.2. Physical Characterization of Crystalline Compound (I) malate Form B

17.2.1 X-Ray Powder Diffraction

The material from Example 17.1 was placed in an XRPD sample holder and measured in accordance with method Ml.

XRPD shows that a unique crystalline material (Form B) was obtained.

FIG. 27 shows the XRPD pattern for Compound (I) malate salt (Form B) measured using reflection! geometry. The most abundant or discriminatory peaks are identified in Table 17. Angle 2-Theta (2Θ) Intensity (%)

8.2 100.0

12.8 41.3

16.4 35.3

26.8 30.9

25.1 26.5

5.5 25.5

14.2 23.0

21.1 22.8

23.7 21.7

22.7 21.6

Table 17. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) malate salt (Form B).

Two characteristic peaks are found at about 2-theta = 8.2°, and 12.8°. Thus, Compound (I) malate salt (Form B) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 8.2° and 12.8°, plus or minus 0.2 °2-theta. Example 18. Preparation of Compound (I) Malate Form C

18.1 Synthesis.

15 mg of Compound (I) malate Form A (Example 16) was suspended in 200 ul of MeOH, the slurry was stirred at ambient temperature for 3 days. The slurry was evaporated in ambient conditions to yield an off-white solid.

18.2. Physical Characterization of Crystalline Compound (I) malate Form C

18.2.1 X-Ray Powder Diffraction

The material from Example 18.1 was placed in an XRPD sample holder and measured in accordance with method Ml. XRPD shows that a unique crystalline material (Form C) was obtained.

FIG. 28 shows the XRPD pattern for Compound (I) malate salt (Form C) measured using reflection! geometry. The most abundant or discriminatory peaks are identified in Table 18.

Table 18. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) malate salt (Form C).

Two characteristic peaks are found at about 2-theta = 8.5°, and 13.2°. Thus, Compound (I) malate salt (Form C) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 8.5° and 13.2°, plus or minus 0.2 °2-theta.

Example 19. Preparation of Compound (I) Malate Form D

19.1 Synthesis.

15 mg of Compound (I) malate Form A (Example 16) was suspended in 0.2 ul of acetone and 0.5 ml of H ₂ 0, the slurry was stirred at ambient temperature for 3 days. The slurry was evaporated in ambient conditions to yield an off-white solid. 19.2. Physical Characterization of Crystalline Compound (I) malate Form D

19.2.1 X-Ray Powder Diffraction

The material from Example 19.1 was placed in an XRPD sample holder and measured in accordance with method Ml .

XRPD shows that a unique crystalline material (Form D) was obtained.

FIG. 29 shows the XRPD pattern for Compound (I) malate salt (Form D) measured using reflection! geometry. The most abundant or discriminatory peaks are identified in Table 19.

Table 19. Ten most prominent X-Ray Powder Diffraction peaks for Compound (I) malate salt (Form D).

Three characteristic peaks are found at about 2-theta = 7.6°, 12.4°, and 26.4°. Thus, Compound (I) malate salt (Form D) is characterized in providing at least one of the following 2Θ values measured using CuKa radiation: 7.6°, 12.4°, and 26.4°, plus or minus 0.2 °2-theta.

Example 20 - Dissolution testing

The dissolution rate and extent was examined using μϋΐ^ Profiler, Pion, and reversed phase gradient LC-UV. 8 mg of free base and free base equivalent of respective salts were weighed out into individual glass μϋΐ^ vials. Acetate buffer pH 5 (0.1M, 20 mL) was then added on top of the drug substance and stirred at 500 rpm at 37°C. The dissolution was monitored by online UV (spectra collected every 30 seconds for 3.3 hours) and samples taken for offline LC-UV analysis at time points indicated in table 20 and used for quantification purposes. To prepare samples for LC-UV analysis, 500 μΐ _^ was taken from each μϋΐ^ vial and spun at 40 000 rpm for 15 minutes at 37°C using Optima Ultracentrifuge, Beckman Coulter. An accurate volume of the supernatant was taken (200 μί) and diluted with acetonitrile (200 μί) for analysis by LC-UV.

The results are shown in figures 30 and 31.

TABLE 20: Concentration (mg/mL) in solution at pH 5 over time of free base and salts

The mesitylene sulfonic acid salt Form A, the malonate salt Form B and the tartrate salt Form A generate a higher concentration of solubilized drug at higher pH compared to the free base and the citrate Form A and fumarate Form A salts, as can be seen in Figure 30. This concentration remains dissolved for at least 3 hours, as can be seen in Figure 31. This increased dissolution rate and supersaturation will likely lead to greater exposure in patients having higher gastric pH. The novel salts forms claimed herein are also expected to show a reduced food effect on GI absorption compared with the free base and the fumarate and citrate salts).