WO2018115965A1 - Formes solides de composés d'imidazopyrazine - Google Patents

Formes solides de composés d'imidazopyrazine Download PDF

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Publication number
WO2018115965A1
WO2018115965A1 PCT/IB2017/001688 IB2017001688W WO2018115965A1 WO 2018115965 A1 WO2018115965 A1 WO 2018115965A1 IB 2017001688 W IB2017001688 W IB 2017001688W WO 2018115965 A1 WO2018115965 A1 WO 2018115965A1
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WIPO (PCT)
Prior art keywords
compound
methoxy
pyrazin
imidazo
benzamide
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PCT/IB2017/001688
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English (en)
Inventor
Dedong Wu
Timothy Gordon INGALLINERA
Jerry Evarts
Eduard Willem De Zwart
Tjeerd Andries Barf
James Francis Mccabe
Saskia VERKAIK
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Acerta Pharma Bv
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Publication of WO2018115965A1 publication Critical patent/WO2018115965A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • 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
  • the invention also relates to a pharmaceutical composition
  • 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
  • diseases mediated by BTK such as cancer, inflammation, immune, and autoimmune diseases.
  • 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-methoxy-N-(pyridin-2-yl)benzamide.
  • 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]pyrazin-l-yl)-2-methoxy-N-(pyridin-2- yl)benzamide Form A.
  • 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.
  • 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 tartrate Form A.
  • 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
  • BTK Bruton Tyrosine Kinase
  • BCR B cell receptor
  • 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
  • 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
  • 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.
  • 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-methoxy-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-methoxy-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-methoxy-N-(pyridin-2-yl)benzamide tartrate, referred to herein as Compound (I) tartrate Form A.
  • novel salt forms of Compound (I) claimed herein e.g. mesitylene sulphonic acid salt Form A, malonate Form B and tartrate Form A
  • 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.
  • GI gastrointestinal
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)-4-
  • 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,
  • 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-(
  • 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)-4-
  • the x-axis shows the 2-theta value and the y-axis the intensity counts.
  • the x-axis shows the temperature ( ° C) and the y- axis the heat flow (W/g).
  • 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
  • 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
  • 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.
  • co-administration 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.
  • an 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.
  • QD means quaque die, once a day, or once daily.
  • BID bis in die, twice a day, or twice daily.
  • TID means bis in die, twice a day, or twice daily.
  • TID means ter in die, three times a day, or three times daily.
  • QID means quater in die, four times a day, or four times daily.
  • 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.
  • acidulant refers to a substance that increases acidity.
  • transmission or “transmission mode,” when used in conjunction with powder X-ray diffraction, refers to the transmission (also known as Debye-Scherrer) sampling mode.
  • reflection or “reflection mode,” when used in conjunction with powder X-ray diffraction, refers to the reflection (also known as Bragg-Brentano) sampling mode.
  • the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • 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.
  • 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.
  • Form B is a hydrate with relatively poor solid-state properties (poor crystallinity and stability).
  • Form A is anhydrous and showed good crystallinity and stability.
  • the Form A polymorph of Compound (I) is expected to have an increased aqueous solubility over the crystalline hydrated Form B.
  • 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.
  • 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 °2 ⁇ , 10.0° ⁇ 0.2 °2 ⁇ and 14.6° ⁇ 0.2 °2 ⁇ .
  • 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 °2 ⁇ , 10.0° ⁇ 0.1 °2 ⁇ and 14.6° ⁇ 0.1 °2 ⁇ .
  • 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°
  • 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 °2 ⁇ , 10.0° ⁇ 0.1 °2 ⁇ and 14.6° ⁇ 0.1 °2 ⁇ .
  • 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
  • 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 °2 ⁇ , 10.0° ⁇ 0.1 °2 ⁇ , 14.6° ⁇ 0.1 °2 ⁇ , 6.2° ⁇ 0.1 °2 ⁇ and 20.0° ⁇ 0.1 °2 ⁇ .
  • 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).
  • intensities in an X-ray powder diffraction pattern may vary depending on measurement conditions and sample preparation.
  • 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 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.
  • 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 °2 ⁇ . 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 °2 ⁇ .
  • 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.
  • 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.
  • 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.
  • 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.
  • the invention provides a crystalline solid form of (S)-4-(8-amino-3-(l-
  • 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.
  • the X-ray powder diffraction pattern of any of the foregoing embodiments is measured in reflection mode.
  • 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.
  • 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 gas
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the invention provides a crystalline solid form of (S)-4-(8-amino-3-(l-
  • 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.
  • the X-ray powder diffraction pattern of any of the foregoing embodiments is measured in reflection mode.
  • composition (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.
  • 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.
  • 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.
  • 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.
  • 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
  • the pharmaceutical compositions are formulated to provide a therapeutically effective amount of a solid form of the BTK inhibitor, as the active ingredient.
  • the pharmaceutical compositions contain one or more pharmaceutically acceptable excipients.
  • the invention provides a pharmaceutical composition comprising crystalline Form A of Compound (1) free base and a pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline Compound (1) mesitylene sulphonic acid salt Form A and a pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition comprising crystalline Compound (1) malonate Form B and a pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition comprising crystalline Compound (1) tartrate Form A and a pharmaceutically acceptable excipient.
  • 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,
  • compositions may function as, for example, adjuvants, diluents, carriers, solubilizers, permeation enhancers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents.
  • 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.
  • the invention provides a process for the preparation of a
  • 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.
  • 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.
  • 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.
  • 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
  • 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%,
  • the concentration of the particular solid form of Compound (1) is the concentration of the particular solid form of Compound (1)
  • compositions of the invention e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate
  • 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.
  • 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
  • the concentration of the particular solid form of Compound (1) is independently in the range from approximately 0.001% to approximately 10%, approximately 0.01% to
  • 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, 0.00
  • 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,
  • 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,
  • HFA heptafluoroalkane
  • intramuscular, intravascular or infusion or by rectal administration in the form of suppositories.
  • 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.
  • 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
  • the cores may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s).
  • the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • 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.
  • 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.
  • excipients known to those skilled in art may be used when making formulations for oral use.
  • 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.
  • 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
  • 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.
  • the composition further contains (iii) an effective amount of another active pharmaceutical ingredient.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable dry kits.
  • 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 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.
  • 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.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • a single dose of a solid form of crystalline Compound (1) of the invention may also be used for treatment of an acute condition.
  • 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.
  • 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
  • the administration of the solid form of the Compound (1) of the invention 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.
  • 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
  • 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
  • the solid form of Compound (1) of the invention is administered chronically on an ongoing basis - e.g., for the treatment of chronic effects.
  • an effective dosage of the particular form of Compound (1) of the invention 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
  • 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.
  • 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.
  • 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
  • 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.
  • the particular form of Compound (1) of the invention 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).
  • QD a dosage of 10 to 400 mg once daily
  • QD 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).
  • the particular form of Compound (1) of the invention 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.
  • the particular form of Compound (1) of the invention 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 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.
  • 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.
  • 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.
  • proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole
  • H 2 receptor antagonists such as cimetidine, ranitidine, and famotidine
  • antacids such as bicarbonates, carbonates, and hydroxides of aluminium, calcium, magnesium
  • 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.
  • 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.
  • the mammal is a human.
  • the hyperproliferative disorder is cancer.
  • 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.
  • 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 lymph
  • 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)).
  • 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)).
  • BPH benign prostatic hypertrophy
  • the hyperproliferative disorder is an inflammatory, immune, or autoimmune disorder.
  • 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, instaenitis suppurativa, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn'
  • the method of any of the foregoing embodiments further includes the step of administering an acid reducing agent to the mammal.
  • 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.
  • proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole
  • H 2 receptor antagonists such as cimetidine, ranitidine, and famotidine
  • antacids such as bi
  • 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., lymphom
  • 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)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)
  • BPH benign prostatic hypert
  • 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
  • MPDs myeloproliferative disorders
  • PV polycythemia vera
  • ET essential thrombocythemia
  • PMF primary myelofibrosis
  • BCR-ABLl-positive chronic neutrophilic leukemia
  • mastocytosis e.g. Form A free base, Form A mesitylene sulphonic acid salt, Form B malonate or Form A tartrate
  • 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.
  • 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
  • age-related macular degeneration and hemangioma.
  • 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.
  • the invention provides a method of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, squamous cell carcinoma including head and neck cancer.
  • 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.
  • a second agent selected from the group consisting of bendamustine, venetoclax, gemcitabine, albumin-bound paclitaxel, rituximab, obinutuzumab, ofatumumab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab.
  • 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
  • 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.
  • 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.
  • 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
  • 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
  • CLL
  • 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
  • BC activated B-cell
  • GCB germinal center B-cell
  • follicle center lymphoma Hodgkin's disease, multiple myeloma, indolent non-Hodgkin' s lymphoma, and mature B-cell ALL.
  • the hyperproliferative disorder is a subtype of CLL.
  • CLL is often classified for immunoglobulin heavy- chain variable-region (IgVH) mutational status in leukemic cells.
  • IgVH immunoglobulin heavy- chain variable-region
  • 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.
  • CLL The methylation of ZAP-70 at CpG3 is also used to characterize CLL, for example by pyro sequencing.
  • 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.
  • 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.
  • 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.
  • 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.
  • the hyperproliferative disorder is a CLL or SLL in a patient, wherein the patient is sensitive to lymphocytosis.
  • 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.
  • the viral infection in any of the foregoing embodiments is selected from the group consisting of infectious mononucleosis, hepatitis, and cytomegalovirus.
  • the bacterial infection in any of the foregoing embodiments is selected from the group consisting of pertussis, tuberculosis, and brucellosis.
  • 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.
  • 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
  • a pharmaceutical composition comprising said crystalline solid
  • 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.
  • 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
  • a pharmaceutical composition comprising said crystalline solid form
  • 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.
  • 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
  • a pharmaceutical composition comprising said crystalline solid
  • Compound (I) citrate Form A 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.
  • Compound (I) fumarate Form B 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.
  • the mammal is a human.
  • the hyperproliferative disorder is cancer.
  • 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.
  • 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
  • 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)).
  • 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)).
  • BPH benign prostatic hypertrophy
  • the hyperproliferative disorder is an inflammatory, immune, or autoimmune disorder.
  • 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, instagren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis
  • the method of any of the foregoing embodiments further includes the step of administering an acid reducing agent to the mammal.
  • 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.
  • proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole
  • H 2 receptor antagonists such as cimetidine, ranitidine, and famotidine
  • antacids such as bi
  • XRPD X-Ray Powder Diffraction
  • XRPD analysis was performed using a Bruker D8 or Brucker D4 diffractometer, which is commercially available from Bruker AXS IncTM (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.
  • XRPD 2 ⁇ 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
  • DSC analysis was performed on samples prepared according to standard methods using a Q SERIESTM 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®.
  • 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
  • LC liquid chromatography
  • MS mass spectrometry
  • UV/Vis (210/240 nm)
  • Eluents (mobile phase): A: acetonitrile, B: acetonitrile / MilliQ-water in MilliQ-water.
  • UV/Vis (210/240 nm)
  • the material was analyzed by XRPD using method Ml.
  • 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 (2 ⁇ ) Intensity (%)
  • Compound (I) free base Form A is characterised in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 7.9°, 10.0° and 14.6°, plus or minus 0.2 °2-theta.
  • 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.
  • 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.
  • 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.
  • Compound (I) free base Form B is characterised in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 10.8° and 12.6°, plus or minus 0.2 °2-theta.
  • 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.
  • 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:
  • Table 3 list of counter ions used in Compound (I) salt screen.
  • 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 ⁇ - 2 ⁇ configuration over the scan range 2° to 40° 2 ⁇ with a nominal 0.12 second exposure per 0.02° increment. The instrument was equipped with a Position sensitive detector (Lynx eye).
  • SSC Bruker single silicon crystal
  • FIG. 5 shows the XRPD pattern for Compound (I) mesitylene sulphonic acid salt (Form
  • 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.
  • Example 5.1 The slurry from Example 5.1 was placed in an XRPD sample holder and measured as the wet cake in accordance with method Ml.
  • 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 (2 ⁇ ) Intensity (%)
  • Compound (I) malonate salt (Form A) is characterized in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 6.9°, 10.9° and 12.4°, plus or minus 0.2 °2-theta.
  • Example 4.1 The material from Example 4.1 was placed in an XRPD sample holder and measured in accordance with method Ml.
  • 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.
  • 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 °2 ⁇ .
  • 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
  • Example 5.1 The material from Example 5.1 was placed in an XRPD sample holder and measured in accordance with method Ml.
  • 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.
  • Compound (I) malonate salt (Form C) is characterized in providing at least one of the following 2 ⁇ 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
  • 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%.
  • Example 8.1 The material from Example 8.1 was placed in an XRPD sample holder and measured in accordance with method Ml.
  • 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.
  • Compound (I) citrate salt (Form A) is characterized in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 7.2°, 9.7° and 11.9°, plus or minus 0.2 °2-theta.
  • Compound (I) citrate Form A 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.
  • 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
  • Example 9.1 The material from Example 9.1 was placed in an XRPD sample holder and measured in accordance with method Ml .
  • 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.
  • Compound (I) citrate salt (Form B) is characterized in providing the following 2 ⁇ values measured using CuKa radiation: 6.9°, 13.7° and 22.8°, plus or minus 0.2 °2-theta.
  • 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.
  • 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%.
  • Example 10.1 The material from Example 10.1 was placed in an XRPD sample holder and measured in accordance with method Ml.
  • 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.
  • Compound (I) tartrate salt (Form A) is characterized in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 8.0° and 11.0°, plus or minus 0.2 °2-theta.
  • 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 11.1 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.
  • 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.
  • Compound (I) tartrate salt (Form B) is characterized in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 7.6° and 15.2°, plus or minus 0.2 °2-theta.
  • Example 12.1 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.
  • Compound (I) tartrate salt (Form C) is characterized in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 17.1°, 25.9° and 26.8°, plus or minus 0.2 °2-theta.
  • 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.
  • Example 13.1 The material from Example 13.1 was placed in an XRPD sample holder and measured in accordance with method Ml .
  • 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.
  • Compound (I) fumarate salt (Form A) is characterized in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 12.4°, 13.3° and 23.4°plus or minus 0.2 °2-theta.
  • 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 14.1 The material from Example 14.1 was placed in an XRPD sample holder and measured in accordance with method Ml.
  • 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.
  • Compound (I) fumarate salt (Form B) is characterized in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 6.2°, 10.0°, and 20.1°, plus or minus 0.2 °2-theta.
  • 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.
  • Compound (I) fumarate Form B 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 15.1 The material from Example 15.1 was placed in an XRPD sample holder and measured in accordance with method Ml .
  • 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.
  • 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 °2 ⁇ .
  • Example 16 Preparation of Compound (I) Malate Form A
  • 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%.
  • Example 16.1 The material from Example 16.1 was placed in an XRPD sample holder and measured in accordance with method Ml.
  • 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.
  • Compound (I) malate salt (Form A) is characterized in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 5.2°and 26.2°, plus or minus 0.2 °2-theta.
  • 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 17.1 The material from Example 17.1 was placed in an XRPD sample holder and measured in accordance with method Ml.
  • 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 (2 ⁇ ) Intensity (%)
  • Compound (I) malate salt (Form B) is characterized in providing at least one of the following 2 ⁇ 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
  • Example 16 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.
  • Example 18.1 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.
  • Compound (I) malate salt (Form C) is characterized in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 8.5° and 13.2°, plus or minus 0.2 °2-theta.
  • Example 19.1 The material from Example 19.1 was placed in an XRPD sample holder and measured in accordance with method Ml .
  • 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.
  • Compound (I) malate salt (Form D) is characterized in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 7.6°, 12.4°, and 26.4°, plus or minus 0.2 °2-theta.
  • 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).

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Abstract

Dans certains modes de réalisation, la présente invention concerne des formes solides cristallines, notamment des polymorphes et des formes salines, de (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5- a]pyrazin-1-yl)-2-méthoxy-N-(pyridin-2-yl)benzamide. Dans certains modes de réalisation, l'invention concerne également des compositions pharmaceutiques contenant les formes solides cristallines, et des procédés pour le traitement d'états de santé ou de troubles par l'administration à un sujet d'une composition pharmaceutique qui comprend lesdites formes, notamment des compositions pharmaceutiques et des procédés pour surmonter les effets d'agents de réduction acide.
PCT/IB2017/001688 2016-12-23 2017-12-19 Formes solides de composés d'imidazopyrazine WO2018115965A1 (fr)

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WO2020043787A1 (fr) * 2018-08-29 2020-03-05 Acerta Pharma B.V. Procédés de préparation de 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)-pyrrolidin-2-yl] imidazo[1,5-a]-pyrazin-1-yl}n-(pyridin-2-yl)-benzamide

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Publication number Priority date Publication date Assignee Title
WO2018229613A1 (fr) * 2017-06-13 2018-12-20 Dr. Reddy's Laboratories Limited Formes solides d'acalabrutinib et procédé de préparation correspondant
WO2020043787A1 (fr) * 2018-08-29 2020-03-05 Acerta Pharma B.V. Procédés de préparation de 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)-pyrrolidin-2-yl] imidazo[1,5-a]-pyrazin-1-yl}n-(pyridin-2-yl)-benzamide
JP2021535220A (ja) * 2018-08-29 2021-12-16 アセルタ・ファーマ・ベスローテン・フェンノートシャップAcerta Pharma B.V. ４−｛８−アミノ−３−［（２Ｓ）−１−（ブタ−２−イノイル）−ピロリジン−２−イル］イミダゾ［１，５−ａ］−ピラジン−１−イル｝Ｎ−（ピリジン−２−イル）−ベンズアミドの調製のためのプロセス
AU2019332882B2 (en) * 2018-08-29 2022-01-27 Acerta Pharma B.V. Processes for the preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)-pyrrolidin-2-yl]imidazo[1,5-a]-pyrazin-1-yl}N-(pyridin-2-yl)-benzamide
AU2022200828B2 (en) * 2018-08-29 2023-05-25 Acerta Pharma B.V. Processes for the preparation of 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)-pyrrolidin-2-yl]imidazo[1,5-a]-pyrazin-1-yl}n-(pyridin-2-yl)-benzamide
AU2023204660B2 (en) * 2018-08-29 2024-01-25 Acerta Pharma B.V. Processes for the preparation of 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)-pyrrolidin-2-yl]imidazo[1,5-a]-pyrazin-1-yl}n-(pyridin-2-yl)-benzamide
JP7439095B2 (ja) 2018-08-29 2024-02-27 アセルタ・ファーマ・ベスローテン・フェンノートシャップ ４－｛８－アミノ－３－［（２Ｓ）－１－（ブタ－２－イノイル）－ピロリジン－２－イル］イミダゾ［１，５－ａ］－ピラジン－１－イル｝Ｎ－（ピリジン－２－イル）－ベンズアミドの調製のためのプロセス

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