Crystalline forms of pyrimidino diazepine derivative

Abstract

To provide new crystalline forms of a pyrimido-diazepine derivative which exhibits excellent anti-tumour activity.SOLUTION: Provided is a crystalline form of compound (I) in the form of a pharmaceutically acceptable salt, or a solvate of the pharmaceutically acceptable salt, or a cocrystal, the crystalline form being a monohydrochloride monohydrate. Provided is also a pharmaceutical composition containing the crystalline form as an active ingredient, and use thereof in the prevention or treatment of disease. Further provided is a process for preparing the crystalline form.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to crystalline forms of pyrimido-diazepine derivatives. The present invention also relates to pharmaceutical compositions containing said crystalline forms as active ingredients and their use in the prevention or treatment of diseases. The present invention further relates to methods for preparing the crystalline forms. [Background technology]

[0002] Polo-like kinases are a family of serine-threonine kinases that are critical regulators of cell cycle progression and DNA damage response (Petronczki et al, Curr Opin Cell Biol. 2008 Dec; 20(6):650-60). PLK1 is frequently overexpressed in cancer, and its levels are significantly increased. PLK1 correlates with aggressiveness and has prognostic value for predicting outcome (Kanaji et al. Oncology. 2006; 70(2):126-33). Cancer cell proliferation is blocked in vitro and in vivo by small molecule PLK1 inhibitors and PLK1 antisense / siRNA (Spankuch et al, Oncogene, 2007 Aug 23; 26(39):5793-807). PLK1 inhibitors cause mitotic arrest and subsequent induction of apoptosis. Due to the central role of PLK1 in mitosis and cell division, rapidly proliferating normal cells are also affected by PLK1 inhibitors. As a result, clinical PLK1 inhibitors have been shown to exhibit a narrow therapeutic window and cause significant hematologic toxicity (Schoffski et al, Eur J Cancer, 2012 Jan; 48(2):179-86). Widening the Therapeutic Window Identification of patient / tumor selectivity markers and treatment regimens that will lead to successful development of these agents is crucial. Mutant TP53 has been shown to be one such predictive marker for sensitivity to PLK1 inhibitors (Degenhardt et al, Clin Cancer Res. 2010 Jan 15; 16(2):384-9).

[0003] Small molecule benzothiazole-3-oxide PLK1 inhibitors and their use in the treatment of proliferative disorders are described in International Patent Application WO 2004 / 067000 in the name of Cyclacel Limited, Inc. In addition, a series of pyrimido-diazepinone molecules have also been shown to potently and selectively inhibit PLK1 (see International Patent Application WO 2009 / 040556; Cyclacel Limited, Inc.), demonstrating strong antiproliferative activity in vitro and in vivo.

[0004] 4-((9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro-[cyclopropane-1,7'-pyrimido[4,5-b][1,4]diazepin]-2'-yl)amino)-3-methoxy-N-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)benzamide or 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5 Compound (I), also known as ',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[4,5-b][1,4]diazepin]-2'-ylamino)-N((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-3-methoxybenzamide, was first disclosed in International Publication WO 2009 / 040556 and has the structure shown below:

[0005] [ka]

[0006] Studies have demonstrated that Compound (I) is a potent inhibitor of polo-like kinase 1 (PLK1), thereby making Compound (I) therapeutically useful in the treatment of a range of proliferative disorders (including, but not limited to, cancer, leukemia, lymphoma, glomerulonephritis, rheumatoid arthritis, and psoriasis), immune-mediated and inflammatory disorders, autoimmune and autoimmune-mediated disorders, renal disorders, and viral disorders.

[0007] Different solid-state forms (including solvated forms) of an active pharmaceutical ingredient may have different properties. Such changes in the properties of different solid-state forms and solvates may provide a basis for improving formulations, for example, by facilitating better processability or handling, improving dissolution profiles, or improving stability (polymorphic and chemical stability) and shelf life. These changes in the properties of different solid-state forms may also result in improvements in the final dosage form, for example, if they serve to improve bioavailability. Different solid-state forms and solvates of an active pharmaceutical ingredient may also give rise to various polymorphic or crystalline forms, which in turn may provide additional opportunities to exploit changes in the properties and characteristics of the solid active pharmaceutical ingredient to provide improved products. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. WO2004 / 067000 Brochure [Patent Document 2] International Publication No. WO2009 / 040556 Pamphlet [Non-patent literature]

[0009] [Non-Patent Document 1] Petronczki et al, Curr Opin Cell Biol. 2008Dec; 20(6):650-60 [Non-patent document 2] Kanaji et al. Oncology. 2006; 70(2):126-33 [Non-patent document 3] Spankuch et al, Oncogene, 2007 Aug 23;26(39):5793-807 [Non-patent document 4] Schoffski et al, Eur J Cancer, 2012 Jan;48(2):179-86 [Non-patent document 5] Degenhardt et al, Clin Cancer Res. 2010 Jan15; 16(2):384-9 Summary of the Invention [Problem to be solved by the invention]

[0010] Discovering new solid-state forms and solvates of a pharmaceutical product may provide materials with desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification, or as desirable intermediate crystalline forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of pharmaceutically useful compounds may also provide opportunities to improve the performance characteristics (dissolution profile, bioavailability, etc.) of pharmaceutical products. It may be possible to obtain different properties, such as a different crystal habit, higher crystallinity, or higher crystallinity, which would provide better processing or handling, an improved dissolution profile, or an improved shelf life. Providing crystallinity or polymorphic stability to the product expands the repertoire of materials available to formulation scientists for formulation optimization. For at least these reasons, there is a need for different solid-state forms of Compound (I). [Means for solving the problem]

[0011] The present invention seeks to provide crystalline forms of Compound (I). In particular, the present invention seeks to provide crystalline forms that retain the desired pharmacological activity of the compound. More specifically, but not exclusively, the present invention seeks to provide crystalline forms of Compound (I) that exhibit one or more improved properties over the amorphous form.

[0012] The present invention relates to solid state forms of Compound (I), in particular salt forms of Compound (I).

[0013] A first aspect of the present invention is a compound (I):

[0014] [ka]

[0015] This relates to the crystalline form of

[0016] Preferably, the compound is in the form of a solvate, a pharmaceutically acceptable salt, or a solvated form of a pharmaceutically acceptable salt, or a co-crystal.

[0017] The crystalline forms of the present invention typically exhibit one or more improved properties over the amorphous form. Suitable properties include, for example, better storage stability, improved ease of handling (flow properties, compressibility, stability), easier purification, improved hygroscopicity profile, and easier synthetic scale-up.

[0018] A second aspect of the present invention relates to a pharmaceutical composition comprising one or more crystalline forms as defined above as an active ingredient and a pharmaceutically acceptable diluent, excipient or carrier.

[0019] A third aspect of the invention relates to one or more crystalline forms as described above for use in medicine.

[0020] A fourth aspect of the invention relates to one or more crystalline forms as described above for use in the prevention or treatment of proliferative disorders, immune-mediated and inflammatory disorders, autoimmune and autoimmune-mediated disorders, renal disorders and viral disorders.

[0021] A fifth aspect of the invention relates to the use of one or more crystalline forms as described above in the preparation of a medicament for the prevention or treatment of proliferative disorders, immune-mediated and inflammatory disorders, autoimmune and autoimmune-mediated disorders, renal disorders and viral disorders.

[0022] A sixth aspect of the present invention relates to a method for the prevention or treatment of proliferative disorders, immune-mediated and inflammatory disorders, autoimmune and autoimmune-mediated disorders, renal disorders and viral disorders, comprising the step of administering to a subject in need thereof a pharmacologically effective amount of one or more crystalline forms as described above.

[0023] A seventh aspect of the present invention relates to a method for preparing a crystalline form as described above.

[0024] An eighth aspect relates to a method for preparing a pharmaceutical composition, said method comprising the step of combining one or more crystalline forms according to the invention with a pharmaceutically acceptable diluent, excipient or carrier.

[0025] The present invention also provides solid state forms of Compound (I) and its salts for use in the preparation of other solid state forms of Compound (I), and / or Compound (I) co-crystals and / or salts and solid state forms thereof.

[0026] The present invention also provides the use of one or more crystalline forms as described herein in the preparation of another solid state form of Compound (I) or a salt thereof or a co-crystal thereof.

[0027] The present invention also relates to a process for preparing another solid state form of Compound (I) or a salt or co-crystal thereof, said process comprising the steps of preparing a crystalline form according to the present invention and converting it to another solid state form of Compound (I) or a salt or co-crystal thereof.

[0028] The present invention also relates to the use of one or more crystalline forms as described herein in the preparation of a pharmaceutical composition.

[0029] The present invention also relates to one or more crystalline forms as described herein for use in the preparation of a pharmaceutical composition. DETAILED DESCRIPTION OF THE INVENTION

[0030] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. Single compounds, such as Compound (I), can be characterized by a variety of parameters, such as melting point, thermal behavior (measured, for example, by thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC)), X-ray powder diffraction (XRPD), and so on. ) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid-state ( 13 C-) have distinguishable crystal structure and physical properties, such as NMR spectrum Various polymorphs may occur. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0031] In particular, the crystalline forms of the present invention may be characterized by a range of different analytical techniques, including X-ray powder diffraction and differential scanning calorimetry. Further details of these techniques and equipment are set out in the Examples section. Preferably, XRPD characterization is performed using a PANalytical diffractometer with CuK α This is done using a line (45 kV, 40 mA). As used herein, unless otherwise specified, XRPD peaks reported herein are those of CuK α XRPD values ​​are given as degrees 2-theta±0.2 degrees 2-theta.

[0032] The solid state forms of Compound (I) and its salts according to the present invention may have advantageous properties selected from at least one of the following: chemical or polymorphic purity, flow properties, solubility, wettability, low hygroscopicity, low solvent (e.g. water) content, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability with respect to polymorphic transformation and thermal and mechanical stability, stability towards dehydration and / or storage stability, lower hygroscopicity, low residual solvent content, and advantageous processability and handling properties such as compressibility or bulk density.

[0033] Crystalline forms may be referred to herein as being characterized by graphical data "as shown in" or "substantially in accordance with" a figure. Such data include, for example, powder X-ray diffractograms and DSC curves. As is well known in the art, graphical data potentially provides additional technical information (a so-called "fingerprint") that further defines distinct solid-state forms that cannot necessarily be described by reference to numerical values ​​or peak positions alone. Those skilled in the art will understand that such graphical representations of data may be subject to slight variations in, for example, peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity. Nevertheless, those skilled in the art will readily be able to compare the graphical data in a figure herein with graphical data generated for an unknown crystalline form and will be able to ascertain whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms. Thus, a crystalline form of Compound (I) represented herein as characterized by graphical data "as shown in" a Figure is understood to encompass any crystalline form of Compound (I) characterized by graphical data having such slight variations as would be known to one of ordinary skill in the art compared to the Figure.

[0034] A solid-state form (or polymorph) may be referred to herein as being polymorphically pure or substantially free of any other solid-state (or polymorphic) form. In this context, the phrase "substantially free of any other form" as used herein will be understood to mean that the solid-state form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or 0% of any other crystalline form of that particular salt of Compound (I), as measured, for example, by XRPD. Thus, a solid-state form of a particular salt of Compound (I) described herein as being substantially free of any other solid-state form of that salt will be understood to contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or 100% of the subject solid-state form.

[0035] As used herein, the term "solvate" or "solvated form" refers to a crystal in which one or more molecules of solvent are associated as an inherent part of the crystal structure. The solvent in a solvate may be present in either a stoichiometric or non-stoichiometric amount. Preferably, the solvate or solvated form is a hydrate, more preferably a monohydrate.

[0036] As used herein, the term "isolated" with respect to the solid state forms of Compound (I) and salts thereof corresponds to a solid state form that is physically separated from the reaction mixture in which it was produced.

[0037] As used herein, the term "anhydrous" in reference to solid-state forms of Compound (I) and its salts corresponds to a solid-state form that does not contain any crystalline water (or other solvent) in a defined stoichiometric amount within the crystal. Typically, an "anhydrous" form does not contain more than 1% (w / w) of either water or organic solvent, as determined, for example, by TGA.

[0038] As used herein, "ambient temperature" means a temperature close to or the same as the temperature of the surrounding space (e.g., room or fume hood) in which the sample is located. Typically, ambient temperature is about 15°C to about 25°C, more preferably about 20°C to about 25°C.

[0039] As used throughout, the term "cooling / cooled" refers to lowering the temperature, e.g., the temperature of a reaction mixture. This term encompasses active methods (e.g., subjecting the reaction mixture to cooling conditions, such as immersing the reaction vessel in a cooling bath) and passive methods, such as allowing the reaction mixture to cool (e.g., to room temperature) by removing the heat source.

[0040] Generally, by changing the crystallization conditions used, different crystalline forms (polymorphs) of the same compound can be produced. These different crystalline forms have different three-dimensional structures and different physicochemical properties. However, the existence of polymorphs is inherently unpredictable, and theoretical calculations for predicting polymorphs are extremely uncertain, and many more polymorphs are predicted than can actually be isolated.

[0041] The present invention encompasses various crystalline forms of pharmaceutically acceptable salts, hydrates and / or co-crystals of Compound (I).

[0042] In one preferred embodiment, the present invention relates to a crystalline form that is a co-crystal or salt formed by the interaction (or reaction) of Compound (I) with an acid selected from hydrochloric acid, maleic acid, L-malic acid, succinic acid, p-toluenesulfonic acid, and hydrobromic acid. The monohydrochloride monohydrate form is particularly preferred.

[0043] In one preferred embodiment, the crystalline form is a co-crystal. As used herein, the term "co-crystal" refers to a crystalline material composed of two or more different molecules, one of which is an active pharmaceutical ingredient (API) and one of which is a co-crystal former ("coformer"), in a defined stoichiometric ratio within the same crystal lattice, associated by non-ionic and non-covalent bonds (see definitions in the FDA Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, February 2018). As used herein, "conformer" refers to a crystalline material composed of two or more different molecules, one of which is an active pharmaceutical ingredient (API) and one of which is a co-crystal former ("coformer"), in a defined stoichiometric ratio within the same crystal lattice, associated by non-ionic and non-covalent bonds (see definitions in the FDA Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, February 2018). " are components that interact non-ionically with the API in the crystal lattice, are not solvents (including water), and are typically non-volatile. Pharmaceutical cocrystals have provided an opportunity to modify the solid-state form of an API beyond traditional solid-state forms, such as salts and polymorphs. Cocrystals can be adapted to improve drug product bioavailability and stability, and to improve the processability of the API during drug product manufacturing.

[0044] Cocrystals are distinguished from salts because, unlike salts, the coexisting components in a cocrystal lattice with a defined stoichiometry interact non-ionically. Furthermore, cocrystals are also distinct from polymorphs, which are 1) single-component crystalline forms with different arrangements or conformations of molecules in the crystal lattice, 2) amorphous forms, and 3) multicomponent phases such as solvates and hydrate forms. Cocrystals are defined to include solvates, hydrates, and coformers. Cocrystals, on the other hand, are more similar to solvates in that both contain more than one component in the lattice. From a physical chemistry perspective, cocrystals can be viewed as special cases of solvates and hydrates in that the second component, the coformer, is not a solvent (including water) and is typically non-volatile.

[0045] Those skilled in the art will appreciate that whether Compound (I) will form a salt or co-crystal with a particular acid will ultimately depend on the relative pKa values.

[0046] Generally speaking, if the API (compound (I)) and its coformer have a ΔpKa (pKa (conjugate acid of base) - pKa (acid)) greater than 1, there will be substantial proton transfer, resulting in ionization and potential formation of a salt as opposed to a cocrystal. On the other hand, if the API and its coformer have a ΔpKa (pKa (conjugate acid of base) - pKa (acid)) less than 1, there will be less than substantial proton transfer. If this criterion is met, the API-coformer is generally classified as a cocrystal.

[0047] In one preferred embodiment, the present invention encompasses crystalline forms of the hydrochloride, maleate, L-malate, succinate, p-toluenesulfonate, and hydrobromide salts of Compound (I). The monohydrochloride monohydrate salt is particularly preferred.

[0048] When a crystalline form of Compound (I) is left undisturbed so as to be open to the atmosphere or mixed with water or a solvent, the crystalline form of Compound (I) may absorb water or the solvent to form a hydrate or solvate. The present invention encompasses these hydrates and solvates as well as anhydrous / non-solvated forms.

[0049] Compound (I) can be prepared according to the procedures described in International Publication No. WO2009 / 040556, as illustrated by Schemes 1-3 in the Examples section.

[0050] In one preferred embodiment, the crystalline form of the present invention can be obtained from a supersaturated solution. The supersaturated solution can be prepared by dissolving a pharmaceutically acceptable salt of Compound (I) in a suitable solvent, optionally adjusting the pH of the solution, concentrating the solution, cooling the solution, or adding a solvent in which the salt of Compound (I) is slightly soluble to a solution of the salt of Compound (I) in a solvent in which Compound (I) is easily soluble.

[0051] In one preferred embodiment, the crystalline salt form is prepared in a single step by combining a solution or suspension of Compound (I) with a solution of a suitable counterion (e.g., HCl, L-malate, succinate, HBr, maleate, or p-toluenesulfonate) and crystallizing the product therefrom.

[0052] In one preferred embodiment, the crystalline salt form is prepared in a single step by treating a solution or suspension of the free base form of Compound (I) with a suitable counterion (e.g., HCl, L-malic acid, succinic acid, HBr, maleic acid, or p-toluenesulfonic acid) and crystallizing the product therefrom. Preferably, the counterion is in the form of a solution, more preferably in the form of a solution containing ethanol or a mixture of ethanol / THF. Preferably, the compound of Formula (I) is in the form of a solution or suspension containing ethanol. Preferably, the counterion is in the form of a solution, more preferably in ethanol or a mixture of ethanol / THF. Preferably, the compound of Formula (I) is in the form of a solution or suspension containing ethanol. More preferably, ethanol is used in an amount of about 5 to about 10 ml, or about 6 to about 9 ml, or about 7 to about 9 ml per gram of Compound (I).

[0053] Preferably, the mixture is heated and then gradually heated in a controlled manner, preferably with stirring. In one preferred embodiment, the process includes the step of adding an antisolvent (preferably ethyl acetate) to aid in crystallization. Preferably, the antisolvent is added before or during the cooling process.

[0054] In one preferred embodiment, the solution or suspension of Compound (I) is heated to a temperature of at least about 70°C, more preferably at least about 75°C, and more preferably from about 75°C to about 85°C. Preferably, the solution or suspension of Compound (I) is heated at this temperature for at least 30 minutes, preferably at least 1 hour. Preferably, the solution or suspension is then cooled to a temperature of about 65°C to about 75°C. Preferably, a counterion solution is added thereto, and the resulting mixture is maintained at 65°C to about 75°C for at least 10 minutes, more preferably at least 30 minutes. Preferably, the mixture is then cooled to a temperature of about 15°C to about 25°C. Preferably, the mixture is maintained at a temperature of about 15°C to about 25°C for at least 2 hours, preferably at least 4 hours, more preferably at least 6 hours, more preferably at least 8 hours, and even more preferably at least 12 hours. In one preferred embodiment, the mixture is further cooled to a temperature of about 0°C to about 10°C. Preferably, the resulting suspension is filtered, washed, and dried.

[0055] In another preferred embodiment, the solution or suspension of Compound (I) is heated to a temperature of at least about 70°C, more preferably at least about 75°C, more preferably about 75°C to about 85°C. Preferably, the solution or suspension of Compound (I) is heated at this temperature for at least 30 minutes, preferably at least 1 hour. Then, a counterion is added thereto. Preferably, the mixture is then cooled to a temperature of about 55°C to about 65°C, more preferably about 60°C. Preferably, the mixture is maintained at this temperature (about 55°C to about 65°C, more preferably about 60°C) for at least 1 hour, more preferably at least 2 hours, even more preferably about 2 hours. Preferably, the mixture is then further cooled to a temperature of about 35°C to about 45°C, more preferably about 40°C. Preferably, the mixture is maintained at this temperature (about 35°C to about 45°C, more preferably about 40°C) for at least 1 hour, more preferably at least 2 hours, even more preferably about 2 hours. Preferably, the mixture is then cooled to a temperature of about 15° C. to about 25° C. Preferably, the mixture is maintained at this temperature (about 15° C. to about 25° C.) for at least 2 hours, preferably at least 4 hours, more preferably at least 6 hours, more preferably at least 8 hours, and even more preferably at least 12 hours. In one preferred embodiment, the mixture is then further cooled to a temperature of about 0 to about 10° C. Preferably, the resulting suspension is filtered, washed, and dried.

[0056] In another preferred embodiment, a suspension of crystalline or amorphous solids of a salt of Compound (I) in a suitable solvent is converted to a slurry and then stirred to convert to the alternative crystalline form, known as solvent-mediated conversion.

[0057] In another preferred embodiment, crystalline precipitation occurs spontaneously within the reaction vessel or can be initiated or accelerated by the addition of crystal seeds, by mechanical stimulation such as through the use of ultrasound, or by scratching the inside of the reaction vessel.

[0058] The temperature for crystallization is typically about 0 to about 100°C, preferably about 5 to about 75°C.

[0059] The precipitated crystals may be collected by filtration, centrifugation or decantation. The isolated crystals may be washed with a suitable solvent.

[0060] The isolated crystals are dried, typically at a temperature of about 10 to about 100°C, preferably about 30 to about 50°C, if necessary, in the presence of a desiccant such as silica gel or calcium chloride, optionally under reduced pressure (e.g., 10 μbar to 50 mbar), until the weight of the crystals becomes constant.

[0061] The dried crystals may absorb water under conditions of about 20 to 90% relative humidity at a temperature of about 10 to about 30°C, preferably about 50 to about 80% relative humidity at a temperature of about 20 to about 30°C, until the weight of the crystalline form becomes constant.

[0062] The crystals obtained according to the present invention can be further purified by recrystallization or slurry purification.

[0063] Recrystallization may be accomplished by techniques well known to those skilled in the art, including the following methods: (1) Cooling method: A salt of compound (I) is dissolved in a hot solvent and the resulting solution is cooled; (2) Concentration method: A solution of a salt of compound (I) is concentrated; (3) Precipitation method: A solvent in which the salt of Compound (I) is slightly soluble is added to a solution of the salt of Compound (I) in a solvent in which the salt of Compound (I) is readily soluble.

[0064] Slurry purification typically involves stirring a suspension of a salt of Compound (I) in a suitable solvent.

[0065] Solvents utilized in the preparation of the crystalline salt form of Compound (I) include ICH Class 2 or preferably Class 3 solvents. For example, esters such as ethyl acetate, alcohols such as ethanol, ketones such as methyl ethyl ketone, ethers such as methyl t-butyl ether, alkanes such as heptane, and water. These solvents may be used alone or as mixtures. Preferred solvents include IMS, acetonitrile, tetralin, cumene, 3-methyl-1-butanol, ethanol, methanol, isopropanol, ethyl acetate, methyl acetate, isopropyl acetate, water, heptane, TBME, THF, MEK, methyl isobutyl ketone, nPrOH, and nBuOAc, and mixtures thereof.

[0066] The present invention encompasses each individual crystalline form as defined above, as well as mixtures with one or more other crystalline forms.

[0067] Crystalline hydrochloride salt In one preferred embodiment of the present invention, the crystalline form is a co-crystal or salt produced by the interaction (or reaction) of hydrochloric acid with Compound (I).

[0068] In one preferred embodiment of the present invention, the crystalline form is the hydrochloride salt of Compound (I). More preferably, the crystalline form is a hydrate, even more preferably the monohydrochloride monohydrate salt.

[0069] In one preferred embodiment, the crystalline form has a pH of 5.57±0.2, 6.19±0.2, 7.97±0.2, 8.32±0.2, 10.48±0.2, 10.72±0.2, 11.83±0.2, 12.53±0.2, 12.74±0.2, 13.34±0.2, 13.86±0.2, 14.69±0.2, 15.62±0.2, 16.02±0.2, 16.75±0.2, 17.02±0.2, 17.42±0.2, 18.19±0.2, 18.81±0.2, 19.08±0.2, 19.49±0.2, 19.83±0.2, 20.15±0.2, 20.55±0.2, 21.12±0.2, 22.82±0.2, 23.78±0.2, 24.68±0.2, 25.10±0.2, 25.70±0.2, 25.86±0.2, 26.86±0.2, 27.92±0.2, 28.53±0.2, It is characterized by an X-ray powder diffraction pattern having two or more diffraction peaks at 2[theta] values ​​selected from 28.92±0.2, 29.71±0.2, 30.80±0.2, 31.56±0.2, 32.38±0.2, 32.98±0.2 and 34.13±0.2.

[0070] In one preferred embodiment, the crystalline form is characterized by having two of the aforementioned diffraction peaks.

[0071] More preferably, the crystalline form is characterized by having 3 or 4 or more, 4 or 5 or more, 5 or 6 or more, or 6 or 7 or more of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20... 40 or 41 or more of the aforementioned diffraction peaks.

[0072] More preferably, the crystalline form is characterized by having 3, 4 or 5 of the aforementioned diffraction peaks.

[0073] In one preferred embodiment, the crystalline form is characterized by having three or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having three of the aforementioned diffraction peaks.

[0074] In one preferred embodiment, the crystalline form is characterized by having four or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having four of the aforementioned diffraction peaks.

[0075] In one preferred embodiment, the crystalline form is characterized by having five or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having five of the aforementioned diffraction peaks.

[0076] In one preferred embodiment, the crystalline form is characterized by having six or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having six of the aforementioned diffraction peaks.

[0077] In one preferred embodiment, the crystalline form is characterized by having 7 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 7 of the aforementioned diffraction peaks.

[0078] In one preferred embodiment, the crystalline form is characterized by having 8 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 8 of the aforementioned diffraction peaks.

[0079] In one preferred embodiment, the crystalline form is characterized by having 9 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 9 of the aforementioned diffraction peaks.

[0080] In one preferred embodiment, the crystalline form is characterized by having 10 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 10 of the aforementioned diffraction peaks.

[0081] Preferably, the crystalline form has a pH of 8.32±0.2, 10.48±0.2, 11.83±0.2, 12.08±0.2, 13.08±0.2, 14.08±0.2, 15.08±0.2, 16.08±0.2, 17.08±0.2, 18.08±0.2, 19.08±0.2, 20.08±0.2, 21.08±0.2, 22.08±0.2, 23.08±0.2, 24.08±0.2, 25.08±0.2, 26.08±0.2, 27.08±0.2, 28.08±0.2, 29.08±0.2, 30.08±0.2, 31. The crystalline form is characterized by an X-ray powder diffraction pattern comprising two or more diffraction peaks at 2[theta] values ​​selected from: 12.53±0.2, 16.02±0.2, 16.75±0.2, 18.19±0.2, 18.81±0.2, 19.49±0.2, 20.55±0.2, and 25.70±0.2. More preferably, the crystalline form is characterized by having 3, 4, or 5 of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having 6, 7, 8, 9, or 10 of the aforementioned diffraction peaks.

[0082] In one highly preferred embodiment, the crystalline form is characterized by an X-ray powder diffraction pattern in which the peak positions substantially correspond to the peak positions of the pattern as shown in Figure 25 or as listed in Table 1. Preferably, the crystalline form is characterized by having 3, 4, 5, or 6 diffraction peaks as shown in Figure 25 or as listed in Table 1.

[0083] In one preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 20°C per minute, exhibiting a maximum endothermic peak at a temperature of from about 265°C to about 275°C, more preferably from about 268°C to about 273°C.

[0084] In one highly preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG.

[0085] In one preferred embodiment, the crystalline form is (a)5.57±0.2, 6.19±0.2, 7.97±0.2, 8.32±0.2, 10.48±0.2, 10.72±0.2, 11 .83±0.2, 12.53±0.2, 12.74±0.2, 13.34±0.2, 13.86±0.2, 14.69±0.2, 15.6 2±0.2, 16.02±0.2, 16.75±0.2, 17.02±0.2, 17.42±0.2, 18.19±0.2, 18.81±0.2, 19.08±0.2, 19.49±0.2, 19.83±0.2, 20.15±0.2, 20.55±0.2, 21.12±0.2 an X-ray powder diffraction pattern having two or more diffraction peaks at 2[theta] values ​​selected from 0.2, 22.82±0.2, 23.78±0.2, 24.68±0.2, 25.10±0.2, 25.70±0.2, 25.86±0.2, 26.86±0.2, 27.92±0.2, 28.53±0.2, 28.92±0.2, 29.71±0.2, 30.80±0.2, 31.56±0.2, 32.38±0.2, 32.98±0.2 and 34.13±0.2, or an X-ray powder diffraction pattern having peak positions as shown in Figure 25; and / or (b) a differential scanning calorimetry trace recorded at a heating rate of 20°C per minute showing a maximum endothermic peak at a temperature between about 265°C and about 275°C, more preferably between about 268°C and about 273°C, or a differential scanning calorimetry trace as shown in Figure 4 It is characterized by:

[0086] In one preferred embodiment, the crystalline form is characterized by (a) and (b) above.

[0087] Advantageously, the crystalline monohydrochloride monohydrate salt / co-crystal of Compound (I), as defined herein, is very slightly hygroscopic (as defined by the classification in Table 9; adapted from Ph.Eur. and Sihorkar et al, Pharmaceutical Dev. & Technol. (2013), 18(2), 348-358). Hygroscopicity Classification).

[0088] In one preferred embodiment, the crystalline form is isolated. In one preferred embodiment, the crystalline form may be isolated by crystallization.

[0089] In one embodiment, the crystalline form is substantially free of any other form.

[0090] A further aspect of the present invention relates to a crystalline form of Compound (I) that is the hydrochloride salt and that contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1%, or no more than about 0% of any other crystalline form of the hydrochloride salt of Compound (I), e.g., as measured by XRPD.

[0091] A further aspect of the present invention relates to a crystalline form of Compound (I) that is the monohydrochloride monohydrate salt and that contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1%, or no more than about 0% of any other crystalline form of the monohydrochloride monohydrate salt of Compound (I), e.g., as measured by XRPD.

[0092] In one preferred embodiment, the crystalline form of the hydrochloride salt of Compound (I) is obtained by the cooling method.

[0093] In one preferred embodiment, the present invention relates to a process for preparing the hydrochloride salt of Compound (I) in crystalline form, comprising the step of crystallizing the hydrochloride salt from a solution of ethanol or an ethanol / THF mixture.

[0094] In one preferred embodiment, the present invention relates to a process for preparing the hydrochloride salt of Compound (I) in crystalline form, comprising treating a solution or suspension of Compound (I) in free base form with HCl to crystallize the product therefrom. Preferably, about 1 to about 1.2 equivalents of HCl are used relative to the compound of formula (I). Preferably, the HCl is in the form of a solution, more preferably comprising ethanol or a mixture of ethanol / THF. Preferably, the compound of formula (I) is in the form of a solution or suspension containing ethanol. In one preferred embodiment, the process comprises adding an antisolvent (preferably ethyl acetate) to aid crystallization. Preferably, the process comprises heating the mixture, followed by gradual cooling, as described above in the detailed description.

[0095] More preferably, the present invention provides a process for preparing a crystalline form of the hydrochloride salt of Compound (I), comprising: (i) preparing a mixture comprising Compound (I) and ethanol and heating the mixture to at least about 70°C; (ii) preparing a solution of hydrochloric acid in ethanol or ethanol / THF and charging it to the mixture produced in step (i); (iii) gradually cooling the mixture produced in step (ii) to ambient temperature. Pu and, (iv) isolating the crystalline form from the mixture; The present invention relates to the method comprising the steps of:

[0096] In one preferred embodiment, EtOAc can be added as an antisolvent before the cooling step. Advantageously, this can increase the yield. An antisolvent is a solvent in which the compound is insoluble or slightly soluble. The use of an antisolvent reduces the solubility of the solute in the solution and induces crystallization.

[0097] More preferably, step (iii) comprises: (a) cooling the mixture produced in step (ii) to about 60°C with stirring and holding at about 60°C for at least 1 hour; (b) Cool the mixture from step (iii) to about 40°C with stirring, and add a little water at about 40°C. and maintaining the temperature for at least one hour. (c) cooling the mixture from step (iv) to ambient temperature and stirring at ambient temperature for at least 12 hours; Includes:

[0098] Preferably, the method comprises the steps of heating a mixture of Compound (I) in ethanol to at least about 75°C, preparing a counterion solution (e.g., HCl) in ethanol or an ethanol / THF mixture and adding it to the ethanolic solution of Compound (I), cooling to about 75°C to about 60°C with stirring and holding for at least 2 hours, cooling to about 40°C and holding for at least 2 hours, and then cooling to ambient temperature and stirring for at least 18 hours, followed by a stepwise cooling to ambient temperature.

[0099] Preferably, the solid is isolated by filtration, more preferably by vacuum filtration. Preferably, the isolated solid is dried in vacuo, preferably for at least 12 hours, or at least 24 hours, at a temperature of at least 40°C, more preferably at least 50°C.

[0100] Another aspect of the present invention relates to products obtainable or obtained by the above process.

[0101] Malate In one preferred embodiment of the present invention, the crystalline form is a co-crystal or salt produced by the interaction (or reaction) of L-malic acid with Compound (I).

[0102] In one preferred embodiment of the present invention, the crystalline form is a malate salt of Compound (I), more preferably an L-malate salt. Preferably, the ratio of L-malic acid to Compound (I) is 2:1, i.e., two molecules of L-malic acid to one molecule of Compound (I).

[0103] In one preferred embodiment, the crystalline form is anhydrous.

[0104] In one preferred embodiment, the crystalline form has a molecular weight of 4.48±0.2, 5.57±0.2, 5.89±0.2, 7.64±0.2, 9.02±0.2, 9.95±0.2, 10.20±0.2, 10.90±0.2, 12.20±0.2, 12.81±0.2, 13.47±0.2, 14.15±0.2, 14.69±0.2, 14.95±0.2, 15.67±0.2, 16.06±0.2, 17.91±0.2, 18.56±0.2, 19.25±0.2, 20.15±0.2 , 20.65±0.2, 21.35±0.2, 21.94±0.2, 22.85±0.2, 24.07±0.2, 24.28±0.2, 24.98±0.2, 25.63±0.2, 26.82±0.2, 27.70±0.2, 29.25±0.2, 30.24±0.2, 31.28±0.2, 32.16±0.2, 33.03±0.2 and 34.47±0.2.

[0105] More preferably, the crystalline form is characterized by having 3 or 4 or more, 4 or 5 or more, 5 or 6 or more, or 6 or 7 or more of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20... 35 or 36 or more of the aforementioned diffraction peaks.

[0106] More preferably, the crystalline form is characterized by having 3, 4 or 5 of the aforementioned diffraction peaks.

[0107] In a more preferred embodiment, the crystalline form is characterized by having two of the aforementioned diffraction peaks.

[0108] In one preferred embodiment, the crystalline form is characterized by having three or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having three of the aforementioned diffraction peaks.

[0109] In one preferred embodiment, the crystalline form is characterized by having four or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having four of the aforementioned diffraction peaks.

[0110] In one preferred embodiment, the crystalline form is characterized by having five or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having five of the aforementioned diffraction peaks.

[0111] In one preferred embodiment, the crystalline form is characterized by having six or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having six of the aforementioned diffraction peaks.

[0112] In one preferred embodiment, the crystalline form is characterized by having 7 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 7 of the aforementioned diffraction peaks.

[0113] In one preferred embodiment, the crystalline form is characterized by having 8 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 8 of the aforementioned diffraction peaks.

[0114] In one preferred embodiment, the crystalline form is characterized by having 9 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 9 of the aforementioned diffraction peaks.

[0115] In one preferred embodiment, the crystalline form is characterized by having 10 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 10 of the aforementioned diffraction peaks.

[0116] Preferably, the crystalline form is characterized by an X-ray powder diffraction pattern comprising two or more diffraction peaks at 2[theta] values ​​selected from 14.69±0.2, 14.95±0.2, 16.06±0.2, 17.91±0.2, 18.56±0.2, 19.25±0.2, 20.15±0.2, 21.94±0.2, 24.07±0.2, and 24.28±0.2. More preferably, the crystalline form is characterized by having three, four, or five of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having six, seven, eight, nine, or ten of the aforementioned diffraction peaks.

[0117] In one highly preferred embodiment, the crystalline form is characterized by an X-ray powder diffraction pattern in which the peak positions substantially correspond to the peak positions of the pattern as shown in Figure 26 or as listed in Table 2. Preferably, the crystalline form is characterized by having 3, 4, 5, or 6 diffraction peaks as shown in Figure 26 or as listed in Table 2.

[0118] In one preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 20° C. per minute, which shows a maximum endothermic peak at a temperature of about 185° C. to about 190° C. and a second, broader peak at about 220° C. Preferably, the maximum endothermic peak is at a temperature of about 186° C. to about 189° C., more preferably about 188° C.

[0119] In one highly preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG.

[0120] In one preferred embodiment, the crystalline form is (a)4.48±0.2, 5.57±0.2, 5.89±0.2, 7.64±0.2, 9.02±0.2, 9.95±0.2, 10.20±0.2, 10.90±0.2, 12.20±0.2, 12.81±0.2, 13.47±0.2, 14. 15±0.2, 14.69±0.2, 14.95±0.2, 15.67±0.2, 16.06±0.2, 17.91±0.2, 18.56±0.2, 19.25±0.2, 20.15±0.2, 20.65±0.2, 21.35±0.2, 21. an X-ray powder diffraction pattern having two or more diffraction peaks at 2[theta] values ​​selected from 94±0.2, 22.85±0.2, 24.07±0.2, 24.28±0.2, 24.98±0.2, 25.63±0.2, 26.82±0.2, 27.70±0.2, 29.25±0.2, 30.24±0.2, 31.28±0.2, 32.16±0.2, 33.03±0.2 and 34.47±0.2, or an X-ray powder diffraction pattern whose peak positions are as shown in Figure 26; and / or (b) A differential scanning calorimetry trace recorded at a heating rate of 20°C per minute showing a maximum endothermic peak at a temperature between about 185°C and about 190°C and a second, broader peak at about 220°C, or the differential scanning calorimetry trace as shown in Figure 6. It is characterized by:

[0121] In one preferred embodiment, the crystalline form is characterized by (a) and (b) above.

[0122] Advantageously, the crystalline L-malate salt / co-crystal of Compound (I), as defined herein, is very slightly hygroscopic (as defined by the classification in Table 9; adapted from Ph. Eur. and Sihorkar et al, Pharmaceutical Dev. & Technol. (2013), 18(2), 348-358). Hygroscopicity Classification).

[0123] In one preferred embodiment, the crystalline form is isolated. In one preferred embodiment, the crystalline form may be isolated by crystallization.

[0124] In one embodiment, the crystalline form is substantially free of any other form.

[0125] A further aspect of the present invention relates to a crystalline form of Compound (I) that is the L-malate salt and that contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1%, or no more than about 0% of any other crystalline form of the L-malate salt of Compound (I), e.g., as measured by XRPD.

[0126] In one preferred embodiment, the crystalline form of the L-malate salt of Compound (I) is obtained by the cooling method.

[0127] In one preferred embodiment, the present invention relates to a process for preparing the L-malate salt of Compound (I) in crystalline form, comprising treating a solution or suspension of Compound (I) in free base form with L-malic acid and crystallizing the product therefrom. Preferably, about 2 to about 2.5, or about 2 to about 2.2, or about 2.2 equivalents of L-malic acid relative to the compound of formula (I) are used. Preferably, the L-malic acid is in the form of a solution, more preferably containing ethanol or a mixture of ethanol / THF. Preferably, the compound of formula (I) is in the form of a solution or suspension containing ethanol. In one preferred embodiment, the method includes the step of adding an antisolvent (preferably ethyl acetate) to aid crystallization. Preferably, the method includes the step of heating the mixture, followed by a step of gradually cooling, as described above in the detailed description.

[0128] In one preferred embodiment, the present invention relates to a process for preparing the L-malate salt of Compound (I) in crystalline form, comprising the step of crystallizing the L-malate salt from a solution of ethanol or an ethanol / THF mixture.

[0129] More preferably, the present invention provides a process for preparing a crystalline form of the L-malate salt of Compound (I), comprising: (i) preparing a mixture comprising Compound (I) and ethanol and heating the mixture to at least about 70°C; (ii) preparing a solution of L-malic acid in ethanol or ethanol / THF and adding it to the mixture produced in step (i); (iii) gradually cooling the mixture produced in step (ii) to ambient temperature. Pu and, (iv) isolating the crystalline form from the mixture; The present invention relates to the method comprising the steps of:

[0130] More preferably, step (iii) comprises: (a) cooling the mixture produced in step (ii) to about 60°C with stirring and holding at about 60°C for at least 1 hour; (b) Cool the mixture from step (iii) to about 40°C with stirring, and add a little water at about 40°C. and maintaining the temperature for at least one hour. (c) cooling the mixture from step (iv) to ambient temperature and stirring at ambient temperature for at least 12 hours; Includes:

[0131] Preferably, the cooling conditions are as defined above for the hydrochloride salt (more specifically the monohydrochloride monohydrate salt).

[0132] Preferably, the solid is isolated by filtration, more preferably by vacuum filtration. Preferably, the isolated solid is dried in vacuo, preferably for at least 12 hours, or at least 24 hours, at a temperature of at least 40°C, more preferably at least 50°C.

[0133] Another aspect of the present invention relates to products obtainable or obtained by the above process.

[0134] Succinate In one preferred embodiment of the present invention, the crystalline form is a co-crystal or salt produced by the interaction (or reaction) of succinic acid with Compound (I).

[0135] In one preferred embodiment of the present invention, the crystalline form is the succinate salt of Compound (I). Preferably, the ratio of succinate to Compound (I) is 2:1, i.e. There is one molecule of compound (I) for every two molecules of succinic acid.

[0136] In one preferred embodiment, the crystalline form is anhydrous.

[0137] In one preferred embodiment, the crystalline form has the following solubility profiles: 3.16±0.2, 5.47±0.2, 9.01±0.2, 10.10±0.2, 11.45±0.2, 12.12±0.2, 12.94±0.2, 13.17±0.2, 14.19±0.2, 14.43±0.2, 14.67±0.2, 15.08±0.2, 15.51±0.2, 15.69±0.2 0.2, 16.76±0.2, 17.55±0.2, 17.69±0.2, 18.54±0.2, 18.95±0.2, 19.52±0.2, 19.84±0.2, 20.30±0.2, 20.45±0.2, 21.04±0.2, 21.36±0.2, 21.83±0.2, 22.12±0.2, 22.76±0.2, 23.11±0.2, 23. 44±0.2, 23.96±0.2, 24.60±0.2, 24.98±0.2, 25.21±0.2, 25.44±0.2, 25.61±0.2, 25.83±0.2, 26.18±0.2, 26.57±0.2, 26.89±0.2, 27.36±0.2, 27.72±0.2, 28.63±0.2, 29.23±0.2, 29.99±0.2 , 30.44±0.2, 30.66±0.2, 31.36±0.2, 31.99±0.2, 32.33±0.2, 32.77±0.2, 33.11±0.2, 33.53±0.2, 34.05±0.2 and 34.50±0.2.

[0138] More preferably, the crystalline form is characterized by having 3 or 4 or more, 4 or 5 or more, 5 or 6 or more, or 6 or 7 or more of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20... 54 or 55 or more of the aforementioned diffraction peaks.

[0139] More preferably, the crystalline form is characterized by having 3, 4 or 5 of the aforementioned diffraction peaks.

[0140] In a more preferred embodiment, the crystalline form is characterized by having two of the aforementioned diffraction peaks.

[0141] In one preferred embodiment, the crystalline form is characterized by having three or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having three of the aforementioned diffraction peaks.

[0142] In one preferred embodiment, the crystalline form is characterized by having four or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having four of the aforementioned diffraction peaks.

[0143] In one preferred embodiment, the crystalline form is characterized by having five or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having five of the aforementioned diffraction peaks.

[0144] In one preferred embodiment, the crystalline form is characterized by having six or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having six of the aforementioned diffraction peaks.

[0145] In one preferred embodiment, the crystalline form is characterized by having 7 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 7 of the aforementioned diffraction peaks.

[0146] In one preferred embodiment, the crystalline form is characterized by having 8 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 8 of the aforementioned diffraction peaks.

[0147] In one preferred embodiment, the crystalline form is characterized by having 9 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 9 of the aforementioned diffraction peaks.

[0148] In one preferred embodiment, the crystalline form is characterized by having 10 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 10 of the aforementioned diffraction peaks.

[0149] Preferably, the crystalline form is characterized by an X-ray powder diffraction pattern comprising two or more diffraction peaks at 2[theta] values ​​selected from 10.10±0.2, 14.67±0.2, 15.08±0.2, 15.51±0.2, 15.69±0.2, 17.55±0.2, 18.54±0.2, 18.94±0.2, 19.52±0.2, and 21.83±0.2. More preferably, the crystalline form is characterized by having three, four, or five of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having six, seven, eight, nine, or ten of the aforementioned diffraction peaks.

[0150] In one highly preferred embodiment, the crystalline form is characterized by an X-ray powder diffraction pattern in which the peak positions substantially correspond to the peak positions of the pattern as shown in Figure 27 or as listed in Table 3. Preferably, the crystalline form is characterized by having 3, 4, 5, or 6 diffraction peaks as shown in Figure 27 or as listed in Table 3.

[0151] In one preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 20° C. per minute, which exhibits a maximum endothermic peak at a temperature of about 185° C. to about 190° C. Preferably, the maximum endothermic peak is at a temperature of about 187° C. to about 190° C., more preferably about 189° C.

[0152] In one highly preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG.

[0153] In one preferred embodiment, the crystalline form is (a)3.16±0.2, 5.47±0.2, 9.01±0.2, 10.10±0.2, 11.45±0.2, 12.12±0.2, 12.94±0.2, 13.17±0.2, 14.19±0.2, 14.43±0.2, 14.67±0.2, 15.08±0.2, 15.51±0.2, 15.69±0.2, 16.76±0.2, 17.55±0.2, 17.69±0.2, 18.54±0.2, 18.95±0.2, 19.52±0.2, 19.84±0.2, 20.30±0.2, 20.45±0.2, 21.04±0.2, 21.36±0.2, 21.83±0.2, 22.12±0.2, 22.76±0.2, 23.11±0.2, 23.44±0.2, 23.96±0.2, 24.60±0.2, 24.98±0.2, 25.21±0.2, 25.44±0.2, 25.61±0.2, 25.83±0.2, 26.18±0.2, 26.57±0.2, 26.89±0.2, 27.36±0.2, 27.72±0.2, 2 [shi] selected from 28.63±0.2, 29.23±0.2, 29.99±0.2, 30.44±0.2, 30.66±0.2, 31.36±0.2, 31.99±0.2, 32.33±0.2, 32.77±0.2, 33.11±0.2, 33.53±0.2, 34.05±0.2 and 34.50±0.2 an X-ray powder diffraction pattern having two or more diffraction peaks at [data] values, or an X-ray powder diffraction pattern having peak positions as shown in Figure 27; and / or (b) A differential scanning calorimetry trace recorded at a heating rate of 20°C per minute showing a maximum endothermic peak at a temperature between about 185°C and about 190°C, or a differential scanning calorimetry trace as shown in Figure 10. It is characterized by:

[0154] In one preferred embodiment, the crystalline form is characterized by (a) and (b) above.

[0155] Advantageously, the crystalline succinate salt / co-crystal of Compound (I) as defined herein is very slightly hygroscopic (as defined by the classification in Table 9; Hygroscopicity Classification adopted from Ph.Eur. and Sihorkar et al, Pharmaceutical Dev. & Technol. (2013), 18(2), 348-358).

[0156] In one preferred embodiment, the crystalline form is isolated. In one preferred embodiment, the crystalline form may be isolated by crystallization.

[0157] In one embodiment, the crystalline form is substantially free of any other form.

[0158] A further aspect of the present invention relates to a crystalline form of Compound (I) that is a succinate salt and that contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1%, or no more than about 0% of any other crystalline form of succinate salt of Compound (I), e.g., as measured by XRPD.

[0159] In one preferred embodiment, the crystalline form of the succinate salt of Compound (I) is obtained by the cooling method.

[0160] In one preferred embodiment, the present invention relates to a method for preparing a crystalline form of succinate salt of Compound (I), comprising treating a solution or suspension of Compound (I) in free base form with succinic acid to crystallize the product therefrom. Preferably, about 2 to about 2.5, or about 2 to about 2.2, or about 2.2 equivalents of succinic acid relative to the compound of Formula (I) are used. Preferably, the succinic acid is in the form of a solution, more preferably containing ethanol or a mixture of ethanol / THF. Preferably, the compound of Formula (I) is in the form of a solution or suspension containing ethanol. In one preferred embodiment, the method comprises adding an antisolvent (preferably ethyl acetate) to aid crystallization. Preferably, the method comprises heating the mixture, followed by stepwise cooling, as described above in the detailed description.

[0161] In one preferred embodiment, the present invention relates to a process for preparing a crystalline form of succinate salt of Compound (I), comprising the step of crystallizing the succinate salt from a solution of ethanol or an ethanol / THF mixture.

[0162] More preferably, the present invention provides a process for preparing a crystalline form of the succinate salt of Compound (I), comprising: (i) preparing a mixture comprising Compound (I) and ethanol and heating the mixture to at least about 70°C; (ii) preparing a solution of succinic acid in ethanol or ethanol / THF and adding it to the mixture produced in step (i); (iii) gradually cooling the mixture produced in step (ii) to ambient temperature. Pu and, (iv) isolating the crystalline form from the mixture; The present invention relates to the method comprising the steps of:

[0163] More preferably, step (iii) comprises: (a) cooling the mixture produced in step (ii) to about 60°C with stirring and holding at about 60°C for at least 1 hour; (b) Cool the mixture from step (iii) to about 40°C with stirring, and add a little water at about 40°C. and maintaining the temperature for at least one hour. (c) cooling the mixture from step (iv) to ambient temperature and stirring at ambient temperature for at least 12 hours; Includes:

[0164] Preferably, the cooling conditions are as defined above for the hydrochloride salt (more specifically the monohydrochloride monohydrate salt).

[0165] Preferably, the solid is isolated by filtration, more preferably by vacuum filtration. Preferably, the isolated solid is dried in vacuo, preferably for at least 12 hours, or at least 24 hours, at a temperature of at least 40°C, more preferably at least 50°C.

[0166] Another aspect of the present invention relates to products obtainable or obtained by the above process.

[0167] Maleate In one preferred embodiment of the present invention, the crystalline form is a co-crystal or salt produced by the interaction (or reaction) of maleic acid with Compound (I).

[0168] In one preferred embodiment of the present invention, the crystalline form is the maleate salt of Compound (I). Preferably, the ratio of maleate to Compound (I) is 2:1, i.e., That is, one molecule of compound (I) for every two molecules of maleic acid.

[0169] In one preferred embodiment, the crystalline form is anhydrous.

[0170] In one preferred embodiment, the crystalline form has the following densities: 4.16±0.2, 5.48±0.2, 7.78±0.2, 9.10±0.2, 9.92±0.2, 10.45±0.2, 10.74±0.2, 11.47±0.2, 12.01±0.2, 12.57±0.2, 13.11±0.2, 14.24±0.2, 14. 86±0.2, 15.17±0.2, 15.76±0.2, 16.28±0.2, 16.68±0.2, 17.22±0.2, 17.94±0.2, 18.13±0.2, 18.25±0.2, 18.71±0.2, 19.04±0.2, 19.47±0.2, 19.71±0.2, 20.11±0.2, 20.8 1±0.2, 21.75±0.2, 21.96±0.2, 22.63±0.2, 23.57±0.2, 24.21±0.2, 24.88±0.2, 25.28±0.2, 25.83±0.2, 26.33±0.2, 26.93±0.2, 27.33±0.2, 27.62±0.2, 28.25±0.2, 29.07±0.2 and 34.31±0.2.

[0171] More preferably, the crystalline form is 3 or 4 or more, 4 or 5 or more, 5 or 6 or more, or 6 or 7 or more of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20... 48 or 49 or more of the aforementioned diffraction peaks.

[0172] More preferably, the crystalline form is characterized by having 3, 4 or 5 of the aforementioned diffraction peaks.

[0173] In a more preferred embodiment, the crystalline form is characterized by having two of the aforementioned diffraction peaks.

[0174] In one preferred embodiment, the crystalline form is characterized by having three or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having three of the aforementioned diffraction peaks.

[0175] In one preferred embodiment, the crystalline form is characterized by having four or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having four of the aforementioned diffraction peaks.

[0176] In one preferred embodiment, the crystalline form is characterized by having five or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having five of the aforementioned diffraction peaks.

[0177] In one preferred embodiment, the crystalline form is characterized by having six or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having six of the aforementioned diffraction peaks.

[0178] In one preferred embodiment, the crystalline form is characterized by having 7 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 7 of the aforementioned diffraction peaks.

[0179] In one preferred embodiment, the crystalline form is characterized by having 8 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 8 of the aforementioned diffraction peaks.

[0180] In one preferred embodiment, the crystalline form is characterized by having 9 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 9 of the aforementioned diffraction peaks.

[0181] In one preferred embodiment, the crystalline form is characterized by having 10 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 10 of the aforementioned diffraction peaks.

[0182] Preferably, the crystalline form is characterized by an X-ray powder diffraction pattern comprising two or more diffraction peaks at 2[theta] values ​​selected from 9.92±0.2, 14.86±0.2, 15.76±0.2, 17.94±0.2, 18.13±0.2, 18.25±0.2, 19.04±0.2, 19.47±0.2, 19.71±0.2, and 24.21±0.2. More preferably, the crystalline form is characterized by having three, four, or five of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having six, seven, eight, nine, or ten of the aforementioned diffraction peaks.

[0183] In one highly preferred embodiment, the crystalline form is characterized by an X-ray powder diffraction pattern in which the peak positions substantially correspond to the peak positions of the pattern as shown in Figure 28 or as listed in Table 4. Preferably, the crystalline form is characterized by having 3, 4, 5, or 6 diffraction peaks as shown in Figure 28 or as listed in Table 4.

[0184] In one preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 20° C. per minute, which exhibits a maximum endothermic peak at a temperature of about 200° C. to about 205° C. Preferably, the maximum endothermic peak is at a temperature of about 202° C. to about 205° C., more preferably about 204° C.

[0185] In one highly preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG.

[0186] In one preferred embodiment, the crystalline form is (a)4.16±0.2, 5.48±0.2, 7.78±0.2, 9.10±0.2, 9.92±0.2, 10.45±0.2, 10.74±0.2, 11. 47±0.2, 12.01±0.2, 12.57±0.2, 13.11±0.2, 14.24±0.2, 14.86±0.2, 15.17±0.2, 15.76 ±0.2, 16.28±0.2, 16.68±0.2, 17.22±0.2, 17.94±0.2, 18.13±0.2, 18.25±0.2, 18.71±0.2, 19.04±0.2, 19.47±0.2, 19.71±0.2, 20.11±0.2, 20.81±0.2, 21.75±0.2, 21.96±0.2. an X-ray powder diffraction pattern having two or more diffraction peaks at 2[theta] values ​​selected from 2, 22.63±0.2, 23.57±0.2, 24.21±0.2, 24.88±0.2, 25.28±0.2, 25.83±0.2, 26.33±0.2, 26.93±0.2, 27.33±0.2, 27.62±0.2, 28.25±0.2, 29.07±0.2, 30.63±0.2, 31.28±0.2, 31.66±0.2, 31.97±0.2, 32.76±0.2, 33.29±0.2, 33.81±0.2 and 34.31±0.2, or an X-ray powder diffraction pattern wherein the peak positions are as shown in FIG. 28; and / or (b) A differential scanning calorimetry trace recorded at a heating rate of 20°C per minute showing a maximum endothermic peak at a temperature between about 200°C and about 205°C, or a differential scanning calorimetry trace as shown in Figure 14. It is characterized by:

[0187] In one preferred embodiment, the crystalline form is characterized by (a) and (b) above.

[0188] Advantageously, the crystalline maleate salt / co-crystal of Compound (I), as defined herein, is very slightly hygroscopic (as defined by the classification in Table 9; adapted from Ph.Eur. and Sihorkar et al, Pharmaceutical Dev. & Technol. (2013), 18(2), 348-358). Hygroscopicity Classification).

[0189] In one preferred embodiment, the crystalline form is isolated. In one preferred embodiment, the crystalline form may be isolated by crystallization.

[0190] In one embodiment, the crystalline form is substantially free of any other form.

[0191] A further embodiment of the invention is the maleate salt, and is measured, for example, by XRPD. The present invention relates to a crystalline form of Compound (I) containing no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1%, or no more than about 0% of any other crystalline form of the maleate salt of Compound (I).

[0192] In one preferred embodiment, the crystalline form of the maleate salt of Compound (I) is obtained by the cooling method.

[0193] In one preferred embodiment, the present invention relates to a method for preparing a crystalline form of the maleate salt of Compound (I), comprising treating a solution or suspension of Compound (I) in free base form with maleic acid to crystallize the product therefrom. Preferably, about 2 to about 2.5, or about 2 to about 2.2, or about 2.2 equivalents of maleic acid relative to the compound of Formula (I) are used. Preferably, the maleic acid is in the form of a solution, more preferably containing ethanol or a mixture of ethanol / THF. Preferably, the compound of Formula (I) is in the form of a solution or suspension containing ethanol. In one preferred embodiment, the method comprises the step of adding an antisolvent (preferably ethyl acetate) to aid crystallization. Preferably, the method comprises the step of heating the mixture, followed by a step of gradually cooling, as described above in the detailed description.

[0194] In one preferred embodiment, the present invention relates to a process for preparing a crystalline form of the maleate salt of Compound (I), comprising the step of crystallizing the maleate salt from a solution of ethanol or an ethanol / THF mixture.

[0195] More preferably, the present invention provides a process for preparing a crystalline form of the maleate salt of Compound (I), comprising: (i) preparing a mixture comprising Compound (I) and ethanol and heating the mixture to at least about 70°C; (ii) preparing a solution of maleic acid in ethanol or ethanol / THF and adding it to the mixture produced in step (i); (iii) gradually cooling the mixture produced in step (ii) to ambient temperature. Pu and, (iv) isolating the crystalline form from the mixture; The present invention relates to the method comprising the steps of:

[0196] More preferably, step (iii) comprises: (a) cooling the mixture produced in step (ii) to about 60°C with stirring and holding at about 60°C for at least 1 hour; (b) Cool the mixture from step (iii) to about 40°C with stirring, and add a little water at about 40°C. and maintaining the temperature for at least one hour. (c) cooling the mixture from step (iv) to ambient temperature and stirring at ambient temperature for at least 12 hours; Includes:

[0197] Preferably, the cooling conditions are as defined above for the hydrochloride salt (more specifically the monohydrochloride monohydrate salt).

[0198] Preferably, the solid is isolated by filtration, more preferably by vacuum filtration. Preferably, the isolated solid is dried in vacuo, preferably for at least 12 hours, or at least 24 hours, at a temperature of at least 40°C, more preferably at least 50°C.

[0199] Another aspect of the present invention relates to a product obtainable or obtained by the above process. .

[0200] Hydrobromide In one preferred embodiment of the present invention, the crystalline form is a co-crystal or salt produced by the interaction (or reaction) of hydrobromic acid with compound (I).

[0201] In one preferred embodiment of the present invention, the crystalline form is the hydrobromide salt of Compound (I), more preferably the monohydrobromide monohydrate salt.

[0202] In one preferred embodiment, the crystalline form has the following densities: 4.23±0.2, 5.38±0.2, 5.66±0.2, 8.11±0.2, 8.31±0.2, 8.61±0.2, 10.02±0.2, 10.45±0.2, 10.75±0.2, 11.32±0.2, 11.98±0.2, 12.45±0.2, 12.60±0.2, 13.10±0.2. 2, 13.94±0.2, 14.71±0.2, 15.76±0.2, 15.91±0.2, 16.26±0.2, 16.72±0.2, 17.00±0.2, 17.24±0.2, 17.64±0.2, 17.97±0.2, 18.91±0.2, 19.19±0.2, 19.51±0.2, 19.76±0.2, 20.05±0.2, 20.1 9±0.2, 20.77±0.2, 21.53±0.2, 22.07±0.2, 22.60±0.2, 23.14±0.2, 23.47±0.2, 24.16±0.2, 24.62±0.2, 25.21±0.2, 25.41±0.2, 25.85±0.2, 26.57±0.2, 26.76±0.2, 27.39±0.2, 28.32±0.2, and characterized by an X-ray powder diffraction pattern having two or more diffraction peaks at 2[theta] values ​​selected from 28.89±0.2, 29.58±0.2, 30.33±0.2, 31.28±0.2, 31.79±0.2, 32.25±0.2, 32.85±0.2, 33.36±0.2, 33.83±0.2 and 34.20±0.2.

[0203] More preferably, the crystalline form is characterized by having 3 or 4 or more, 4 or 5 or more, 5 or 6 or more, or 6 or 7 or more of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20... 54 or 55 or more of the aforementioned diffraction peaks.

[0204] More preferably, the crystalline form is characterized by having 3, 4 or 5 of the aforementioned diffraction peaks.

[0205] In a more preferred embodiment, the crystalline form is characterized by having two of the aforementioned diffraction peaks.

[0206] In one preferred embodiment, the crystalline form is characterized by having three or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having three of the aforementioned diffraction peaks.

[0207] In one preferred embodiment, the crystalline form is characterized by having four or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having four of the aforementioned diffraction peaks.

[0208] In one preferred embodiment, the crystalline form is characterized by having five or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having five of the aforementioned diffraction peaks.

[0209] In one preferred embodiment, the crystalline form is characterized by having six or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having six of the aforementioned diffraction peaks.

[0210] In one preferred embodiment, the crystalline form is characterized by having 7 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 7 of the aforementioned diffraction peaks.

[0211] In one preferred embodiment, the crystalline form is characterized by having 8 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 8 of the aforementioned diffraction peaks.

[0212] In one preferred embodiment, the crystalline form is characterized by having 9 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 9 of the aforementioned diffraction peaks.

[0213] In one preferred embodiment, the crystalline form is characterized by having 10 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 10 of the aforementioned diffraction peaks.

[0214] Preferably, the crystalline form is characterized by an X-ray powder diffraction pattern comprising two or more diffraction peaks at 2[theta] values ​​selected from 10.45±0.2, 10.75±0.2, 11.98±0.2, 16.72±0.2, 17.97±0.2, 18.91±0.2, 19.19±0.2, 19.51±0.2, 25.21±0.2, and 25.41±0.2. More preferably, the crystalline form is characterized by having three, four, or five of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having six, seven, eight, nine, or ten of the aforementioned diffraction peaks.

[0215] In one highly preferred embodiment, the crystalline form is characterized by an X-ray powder diffraction pattern in which the peak positions substantially correspond to the peak positions of the pattern as shown in Figure 29 or as listed in Table 5. Preferably, the crystalline form is characterized by having 3, 4, 5, or 6 diffraction peaks as shown in Figure 29 or as listed in Table 5.

[0216] In one preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 20°C per minute, which exhibits a maximum endothermic peak at a temperature of about 248°C to about 253°C. Preferably, the maximum endothermic peak is at a temperature of about 249°C to about 251°C, more preferably about 250°C.

[0217] In one highly preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG.

[0218] In one preferred embodiment, the crystalline form is (a)4.23±0.2, 5.38±0.2, 5.66±0.2, 8.11±0.2, 8.31±0.2, 8.61±0.2, 10.02±0.2, 10. 45±0.2, 10.75±0.2, 11.32±0.2, 11.98±0.2, 12.45±0.2, 12.60±0.2, 13.10±0.2, 13. 94±0.2, 14.71±0.2, 15.76±0.2, 15.91±0.2, 16.26±0.2, 16.72±0.2, 17.00±0.2, 17.24±0.2, 17.64±0.2, 17.97±0.2, 18.91±0.2, 19.19±0.2, 19.51±0.2, 19.76±0.2, 20. 05±0.2, 20.19±0.2, 20.77±0.2, 21.53±0.2, 22.07±0.2, 22.60±0.2, 23.14±0.2, 23.47±0.2, 24.16±0.2, 24.62±0.2, 25.21±0.2, 25.41±0.2, 25.85±0.2, 26.57±0.2, 26.76±0.2, 27.39±0.2, 28.32±0.2, 28.89±0. an X-ray powder diffraction pattern having two or more diffraction peaks at 2[theta] values ​​selected from 2, 29.58±0.2, 30.33±0.2, 31.28±0.2, 31.79±0.2, 32.25±0.2, 32.85±0.2, 33.36±0.2, 33.83±0.2 and 34.20±0.2, or an X-ray powder diffraction pattern whose peak positions are as shown in Figure 29; and / or (b) A differential scanning calorimetry trace recorded at a heating rate of 20°C per minute showing a maximum endothermic peak at a temperature between about 248°C and about 253°C, or a differential scanning calorimetry trace as shown in Figure 18. It is characterized by:

[0219] In one preferred embodiment, the crystalline form is characterized by (a) and (b) above.

[0220] Advantageously, the crystalline hydrobromide salt / co-crystal of Compound (I), as defined herein, is very slightly hygroscopic (as defined by the classification in Table 9; adapted from Ph.Eur. and Sihorkar et al, Pharmaceutical Dev. & Technol. (2013), 18(2), 348-358). Hygroscopicity Classification).

[0221] In one preferred embodiment, the crystalline form is isolated. In one preferred embodiment, the crystalline form may be isolated by crystallization.

[0222] In one embodiment, the crystalline form is substantially free of any other form.

[0223] A further aspect of the present invention relates to a crystalline form of Compound (I) that is the hydrobromide salt and that contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1%, or no more than about 0% of any other crystalline form of the hydrobromide salt of Compound (I), e.g., as measured by XRPD.

[0224] A further aspect of the present invention relates to a crystalline form of Compound (I) that is the monohydrobromide monohydrate salt and that contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1%, or no more than about 0% of any other crystalline form of the monohydrobromide monohydrate salt of Compound (I), e.g., as measured by XRPD.

[0225] In one preferred embodiment, the crystalline form of the hydrobromide salt of Compound (I) is obtained by the cooling method.

[0226] In one preferred embodiment, the present invention relates to a method for preparing a crystalline form of the hydrobromide salt of Compound (I), comprising treating a solution or suspension of Compound (I) in free base form with hydrobromic acid to crystallize the product therefrom. Preferably, about 1 to about 1.2 equivalents of HBr are used relative to the compound of formula (I). Preferably, the hydrobromic acid is in the form of a solution, more preferably comprising ethanol or a mixture of ethanol / THF. Preferably, the compound of formula (I) is in the form of a solution or suspension containing ethanol. In one preferred embodiment, the method comprises the step of adding an antisolvent (preferably ethyl acetate) to aid crystallization. Preferably, the method comprises the step of heating the mixture, followed by a step of gradually cooling, as described above in the detailed description.

[0227] In one preferred embodiment, the present invention relates to a process for preparing the hydrobromide salt of Compound (I) in crystalline form, comprising the step of crystallizing the hydrobromide salt from a solution of ethanol or an ethanol / THF mixture.

[0228] More preferably, the present invention provides a process for preparing a crystalline form of the hydrobromide salt of Compound (I), comprising: (i) preparing a mixture comprising Compound (I) and ethanol and heating the mixture to at least about 70°C; (ii) preparing a solution of hydrobromic acid in ethanol or ethanol / THF and charging it to the mixture produced in step (i); (iii) gradually cooling the mixture produced in step (ii) to ambient temperature. Pu and, (iv) isolating the crystalline form from the mixture; The present invention relates to the method comprising the steps of:

[0229] More preferably, step (iii) comprises: (a) cooling the mixture produced in step (ii) to about 60°C with stirring and holding at about 60°C for at least 1 hour; (b) Cool the mixture from step (iii) to about 40°C with stirring, and add a little water at about 40°C. and maintaining the temperature for at least one hour. (c) cooling the mixture from step (iv) to ambient temperature and stirring at ambient temperature for at least 12 hours; Includes:

[0230] Preferably, the cooling conditions are as defined above for the hydrochloride salt (more specifically the monohydrochloride monohydrate salt).

[0231] Preferably, the solid is isolated by filtration, more preferably by vacuum filtration. Preferably, the isolated solid is dried in vacuo, preferably for at least 12 hours, or at least 24 hours, at a temperature of at least 40°C, more preferably at least 50°C.

[0232] Another aspect of the present invention relates to products obtainable or obtained by the above process.

[0233] p-Toluenesulfonate In one preferred embodiment of the present invention, the crystalline form is a co-crystal or salt produced by the interaction (or reaction) of p-toluenesulfonic acid with Compound (I).

[0234] In one preferred embodiment of the present invention, the crystalline form is p-toluenesulfonate salt of Compound (I). Preferably, the ratio of Compound (I) to p-toluenesulfonate is 1:1.

[0235] In one preferred embodiment, the crystalline form is anhydrous.

[0236] In one preferred embodiment, the crystalline form has a pH of 5.56±0.2, 7.91±0.2, 8.15±0.2, 8.76±0.2, 10.10±0.2, 10.29±0.2, 10.42±0.2, 12.17±0.2, 12.56±0.2, 13.61±0.2, 13.82±0.2, 14.00±0.2, 14.65±0.2, 14.89±0.2, 15.00±0.2, 15.45±0.2, 15.92±0.2, 16.40±0.2, 16.66±0.2, 16.89±0.2, 17.03±0.2, 17.38±0.2, 17.63±0.2, 17.85±0.2, 18.29±0.2, 19.10±0.2, 19.42±0.2, 19.89±0.2, 20.14±0.2, 20.54±0.2, 20.73±0.2, 21.26±0.2, 21.65±0.2, 21.92±0.2, 22.47±0.2, 23.96±0.2, 24.77±0.2, 25.06±0.2. 2, 25.60±0.2, 26.05±0.2, 26.57±0.2, 27.02±0.2, 27.26±0.2, 27.88±0.2, 28.27±0.2, 29.21±0.2, 29.79±0.2, 30.13±0.2, 31.44±0.2, 32.28±0.2, 34.03±0.2 and 34.67±0.2.

[0237] More preferably, the crystalline form is characterized by having 3 or 4 or more, 4 or 5 or more, 5 or 6 or more, or 6 or 7 or more of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20... 51 or 52 or more of the aforementioned diffraction peaks.

[0238] More preferably, the crystalline form is characterized by having 3, 4 or 5 of the aforementioned diffraction peaks.

[0239] In a more preferred embodiment, the crystalline form is characterized by having two of the aforementioned diffraction peaks.

[0240] In one preferred embodiment, the crystalline form is characterized by having three or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having three of the aforementioned diffraction peaks.

[0241] In one preferred embodiment, the crystalline form is characterized by having four or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having four of the aforementioned diffraction peaks.

[0242] In one preferred embodiment, the crystalline form is characterized by having five or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having five of the aforementioned diffraction peaks.

[0243] In one preferred embodiment, the crystalline form is characterized by having six or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having six of the aforementioned diffraction peaks.

[0244] In one preferred embodiment, the crystalline form is characterized by having 7 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 7 of the aforementioned diffraction peaks.

[0245] In one preferred embodiment, the crystalline form is characterized by having 8 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 8 of the aforementioned diffraction peaks.

[0246] In one preferred embodiment, the crystalline form is characterized by having 9 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 9 of the aforementioned diffraction peaks.

[0247] In one preferred embodiment, the crystalline form is characterized by having 10 or more of the aforementioned diffraction peaks. In a more preferred embodiment, the crystalline form is characterized by having 10 of the aforementioned diffraction peaks.

[0248] Preferably, the crystalline form is characterized by an X-ray powder diffraction pattern comprising two or more diffraction peaks at 2[theta] values ​​selected from 10.42±0.2, 12.17±0.2, 12.56±0.2, 17.63±0.2, 18.29±0.2, 19.10±0.2, 19.89±0.2, 20.14±0.2, 20.54±0.2, and 22.47±0.2. More preferably, the crystalline form is characterized by having three, four, or five of the aforementioned diffraction peaks. More preferably, the crystalline form is characterized by having six, seven, eight, nine, or ten of the aforementioned diffraction peaks.

[0249] In one highly preferred embodiment, the crystalline form is characterized by an X-ray powder diffraction pattern in which the peak positions substantially correspond to the peak positions of the pattern as shown in Figure 30 or as listed in Table 6. Preferably, the crystalline form is characterized by having 3, 4, 5, or 6 diffraction peaks as shown in Figure 30 or as listed in Table 6.

[0250] In one preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 20° C. per minute, which exhibits a maximum endothermic peak at a temperature of about 235° C. to about 240° C. Preferably, the maximum endothermic peak is at a temperature of about 238° C. to about 240° C., more preferably about 239° C.

[0251] In one highly preferred embodiment, the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG.

[0252] In one preferred embodiment, the crystalline form is (a) 5.56±0.2, 7.91±0.2, 8.15±0.2, 8.76±0.2, 10.10±0.2, 10.29±0.2, 10.42±0.2, 12.17± 0.2, 12.56±0.2, 13.61±0.2, 13.82±0.2, 14.00±0.2, 14.65±0.2, 14.89±0.2, 15.00±0.2, 1 5.45±0.2, 15.92±0.2, 16.40±0.2, 16.66±0.2, 16.89±0.2, 17.03±0.2, 17.38±0.2, 17.63±0.2, 17.85±0.2, 18.29±0.2, 19.10±0.2, 19.42±0.2, 19.89±0.2, 20.14±0.2, 20.54±0.2, 20.64±0.2 .73±0.2, 21.26±0.2, 21.65±0.2, 21.92±0.2, 22.47±0.2, 23.96±0.2, 24.77±0.2, 25.06±0.2, 25.60±0.2, 26.05±0.2, 26.57±0.2, 27.02±0.2, 27.26±0.2, 27.88±0.2, 28.27±0.2, 29. an X-ray powder diffraction pattern having two or more diffraction peaks at 2[theta] values ​​selected from 21±0.2, 29.79±0.2, 30.13±0.2, 31.44±0.2, 32.28±0.2, 34.03±0.2, and 34.67±0.2, or an X-ray powder diffraction pattern whose peak positions are as shown in Figure 30; and / or (b) A differential scanning calorimetry trace recorded at a heating rate of 20°C per minute showing a maximum endothermic peak at a temperature between about 235°C and about 240°C, or a differential scanning calorimetry trace as shown in Figure 22. It is characterized by:

[0253] In one preferred embodiment, the crystalline form is characterized by (a) and (b) above. It can be attached.

[0254] Advantageously, the crystalline p-toluenesulfonate salt / co-crystal of Compound (I), as defined herein, is very slightly hygroscopic (as defined by the classification in Table 9; Ph. Eur. and Sihorkar et al, Pharmaceutical Dev. & Technol. (2013), 18(2), 348-358). Hygroscopicity Classification adopted from

[0255] In one preferred embodiment, the crystalline form is isolated. In one preferred embodiment, the crystalline form may be isolated by crystallization.

[0256] In one embodiment, the crystalline form is substantially free of any other form.

[0257] A further aspect of the present invention relates to a crystalline form of Compound (I) that is a p-toluenesulfonate salt and that contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1%, or no more than about 0% of any other crystalline form of the p-toluenesulfonate salt of Compound (I), as measured, for example, by XRPD.

[0258] In one preferred embodiment, the crystalline form of the p-toluenesulfonic acid salt of Compound (I) is obtained by the cooling method.

[0259] In one preferred embodiment, the present invention relates to a process for preparing a crystalline form of p-toluenesulfonate salt of Compound (I), comprising the step of crystallizing p-toluenesulfonate salt from a mixture of ethanol / THF.

[0260] In one preferred embodiment, the present invention relates to a method for preparing a crystalline form of p-toluenesulfonate salt of Compound (I), comprising treating a solution or suspension of Compound (I) in free base form with p-toluenesulfonic acid to crystallize the product therefrom. Preferably, about 1 to about 1.2 equivalents of p-toluenesulfonic acid are used relative to the compound of Formula (I). Preferably, the p-toluenesulfonic acid is in the form of a solution, more preferably comprising ethanol or a mixture of ethanol / THF. Preferably, the compound of Formula (I) is in the form of a solution or suspension comprising ethanol or a mixture of ethanol / THF. In one preferred embodiment, the method comprises adding an antisolvent (preferably ethyl acetate) to aid crystallization. Preferably, the method comprises heating the mixture, followed by gradual cooling, as described above in the detailed description.

[0261] More preferably, the present invention provides a process for preparing a crystalline form of the p-toluenesulfonate salt of Compound (I), comprising: (i) preparing a mixture comprising Compound (I), ethanol, and THF and heating it to at least about 55°C while stirring; (ii) preparing a solution of p-toluenesulfonic acid in ethanol and adding it to the mixture produced in step (i); (iii) cooling the mixture produced in step (ii) to ambient temperature and The step of stirring for 8 hours, (iv) Reducing the volume of solvent in the mixture from step (iii) under a stream of nitrogen to form a suspension. and stirring for at least 1 hour. (v) adding ethanol to the suspension of step (iv) and stirring for at least 12 hours; (vi) isolating the solid from step (v); The present invention relates to the method comprising the steps of:

[0262] Preferably, the ratio of THF to EtOH is at least 3:1, more preferably at least 4:1, more preferably at least 5:1, more preferably at least 6:1, more preferably at least 7:1, more preferably at least 8:1, more preferably at least 9:1, more preferably at least 10:1.

[0263] In one preferred embodiment, the ratio of THF to EtOH is about 3:1, more preferably about 4:1, more preferably about 5:1, more preferably about 6:1, more preferably about 7:1, more preferably about 8:1, more preferably about 9:1, more preferably about 7.5:1.

[0264] More preferably, the method comprises: (i) preparing a mixture comprising Compound (I), ethanol, and THF and heating it to at least about 60° C. while stirring; (ii) preparing a solution of p-toluenesulfonic acid in ethanol and adding it to the mixture produced in step (i); (iii) cooling the mixture produced in step (ii) to ambient temperature and 0 hour stirring step, (iv) Reducing the volume of solvent in the mixture from step (iii) under a stream of nitrogen to form a suspension. and stirring for at least 3 hours. (v) adding ethanol to the suspension of step (iv) and stirring for at least 20 hours; (vi) isolating the solid from step (v); Includes:

[0265] Preferably, the solid is isolated by filtration, more preferably by vacuum filtration. Preferably, the isolated solid is dried in vacuo, preferably for at least 12 hours, or at least 24 hours, at a temperature of at least 40°C, more preferably at least 50°C.

[0266] Another aspect of the present invention relates to products obtainable or obtained by the above process.

[0267] therapeutic use Compound (I) has been shown to exhibit potent inhibitory activity against polo-like kinases, more specifically PLK1, and is therefore useful in the treatment of proliferative disorders (such as cancer, leukemia, lymphoma, and alopecia), immune-mediated and inflammatory disorders (such as graft-versus-host disease (GvHD), graft rejection, and psoriasis), autoimmune and autoimmune-mediated disorders (such as Hashimoto's thyroid disease), and rheumatoid arthritis (rheumatoid arthritis). inflammation, pernicious anemia, Addison's disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, drug-induced lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome and Graves' disease, pemphigus vulgaris, etc.), kidney disorders (glomerulonephritis, nephronophthisis and polycystic kidney disease, etc.), viral disorders (influenza virus, hepatitis B virus (HBV), hepatitis C virus (HCV) It is thought to be useful in the treatment of viruses such as hepatitis C virus (V), human cytomegalovirus (HCMV), and human immunodeficiency virus type 1 (HIV-1).

[0268] Thus, one aspect of the present invention relates to a crystalline form, or a pharmaceutical composition, as described herein, for use in medicine or as a medicament.

[0269] Yet another aspect of the invention relates to a crystalline form, or a pharmaceutical composition, as described herein, for use in the prevention or treatment of a proliferative disorder.

[0270] Another aspect of the invention relates to the use of a crystalline form as described above in the preparation of a medicament for the prevention or treatment of a proliferative disorder.

[0271] Another aspect of the present invention relates to a method for the prevention or treatment of a proliferative disorder, comprising the step of administering to a subject in need thereof a pharmacologically effective amount of a crystalline form, or a pharmaceutical composition as described herein.

[0272] Preferably, the subject is a warm-blooded animal, even more preferably a mammal, even more preferably a human.

[0273] As used herein, the phrase "preparation of a pharmaceutical product" encompasses the use of one or more of the above forms directly as a pharmaceutical product, in addition to its use in screening programs for additional antiproliferative agents or at any stage in the manufacture of such pharmaceutical products.

[0274] One preferred embodiment relates to the use of one or more compounds of the present invention in the treatment of a proliferative disorder. Preferably, the proliferative disorder is cancer, leukemia, or lymphoma. The term proliferative disorder is used herein in a broad sense to include any disorder that requires cell cycle control, for example, inherited proliferative disorders such as polycystic kidney disease.

[0275] As defined herein, an anti-proliferative effect within the scope of the present invention may be demonstrated by the ability to inhibit cell proliferation in an in vitro whole cell assay. Such an assay may be used to determine whether a compound is anti-proliferative in the context of the present invention.

[0276] In one preferred embodiment, the proliferative disorder is a solid tumor. Preferably, the solid tumor is bladder cancer, bone cancer, brain or nerve cancer, prostate cancer, skin cancer, lung cancer, breast cancer, colorectal, ovarian or uterine cancer, or esophageal cancer.

[0277] In another preferred embodiment, the proliferative disorder is a blood cancer. Preferably, the blood cancer is leukemia or lymphoma, more preferably advanced leukemia or myelodysplastic syndromes (MDS). Other examples include acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL).

[0278] In another preferred embodiment, the proliferative disorder is selected from glomerulonephritis, rheumatoid arthritis, and psoriasis.

[0279] Another aspect of the invention relates to a crystalline form or a pharmaceutical composition as described herein for use in the prevention or treatment of an immune-mediated or inflammatory disorder, more preferably the disorder is selected from graft-versus-host disease (GvHD), graft rejection and psoriasis.

[0280] Another aspect of the invention relates to a crystalline form or pharmaceutical composition as described herein for use in the prevention or treatment of an autoimmune or autoimmune-mediated disorder, more preferably the disorder is selected from Hashimoto's thyroiditis, pernicious anemia, Addison's disease, type I diabetes, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, drug-induced lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome and Graves' disease, and pemphigus vulgaris.

[0281] Another aspect of the invention relates to a crystalline form or a pharmaceutical composition as described herein for use in the prevention or treatment of kidney disorders, more preferably wherein the disorder is selected from glomerulonephritis, nephronophthisis and polycystic kidney disease.

[0282] Another aspect of the invention relates to a crystalline form or a pharmaceutical composition as described herein for use in the prevention or treatment of a viral disorder, more preferably the disorder is selected from influenza virus, hepatitis B virus (HBV), hepatitis C virus (HCV), human cytomegalovirus (HCMV) and human immunodeficiency virus type 1 (HIV-1).

[0283] Pharmaceutical Composition When the crystalline form of the present invention is used as a pharmaceutical, preferably as an agent for the treatment or prevention of a proliferative disorder, the crystalline form may be administered alone or as a mixture of the crystalline form with suitable pharmacologically acceptable excipients and / or diluents and / or carriers.

[0284] Therefore, another aspect of the present invention relates to a pharmaceutical composition comprising a crystalline form according to the invention as described above and a pharmaceutically acceptable diluent, excipient or carrier.

[0285] A further aspect relates to a method for preparing a pharmaceutical composition as described above, said method comprising the step of admixing a crystalline form according to the invention with a pharmaceutically acceptable diluent, excipient or carrier.

[0286] Compositions according to the invention may be in unit dosage form such as tablets, capsules, granules, powders, syrups, injections, ointments, solutions, suspensions, aerosols, lozenges or the like for oral, topical (e.g. for psoriasis) or parenteral administration.

[0287] The choice of pharmaceutical carrier, excipient, or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient, or diluent any suitable binders, lubricants, suspending agents, coating agents, solubilizing agents. The pharmaceutical compositions may be for human or animal use in human and veterinary medicine.

[0288] In one preferred embodiment, the pharmaceutical composition is in solid form.

[0289] The pharmaceutical compositions can be prepared in a known manner by using additives such as excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, suspending agents, diluents and solvents.

[0290] Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein can be found in "Handbook of Pharmaceutical Excipients, 2000." nd Edition, (1994), Edited by A. Wade and P. J. Weller. Examples of excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol, or sorbitol; starch derivatives such as corn starch, potato starch, pregelatinized starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and internally cross-linked sodium carboxymethyl cellulose; acacia; dextran; pullulan; silicate derivatives such as light silicic acid anhydride, synthetic aluminum silicate, and magnesium aluminometasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; or the like.

[0291] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro, editor. 1985). Examples of suitable carriers include lactose, starch, glucose, methylcellulose, cellulose acetate, cellulose acetate, cellulose acetate, cellulose acetate esters ... Suitable diluents include ethyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water.

[0292] Examples of disintegrants include the excipients previously described herein, chemically modified starch or cellulose derivatives such as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or the like.

[0293] Preservatives, stabilizers, dyes, and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0294] Examples of stabilizers include para-hydroxybenzoic acid ester derivatives such as methylparaben and propylparaben; alcohol derivatives such as chlorobutanol, benzyl alcohol, and phenethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid; or the like.

[0295] Examples of flavoring agents include all commonly used sweeteners, sour agents, and flavoring agents or the like.

[0296] Examples of solvents include water, ethanol, glycerin, or the like.

[0297] Examples of suitable binders include the excipients described herein above; gelatin; polyvinylpyrrolidone; macrogol; or the like, starch, glucose, anhydrous lactose, free-flow lactose, beta-lactose, natural sugars such as corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol.

[0298] Examples of lubricants include talc; stearic acid; metal stearate derivatives such as calcium stearate, magnesium stearate, sodium stearate; colloidal silica; veegum; waxes such as beeswax or spermaceti; boric acid; glycol; carboxylic acid derivatives such as fumaric acid, adipic acid; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid derivatives such as silicic anhydride, silicic acid hydrate; starch derivatives as mentioned above as excipients; sodium oleate, sodium acetate, sodium chloride, or the like.

[0299] Administration The pharmaceutical compositions of the present invention may be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual administration routes.

[0300] For oral administration, particular use consists in compressed tablets, pills, tablets, gels, drops, and capsules. Preferably, these compositions contain 1 to 250 mg, more preferably 10 to 100 mg, of active ingredient per dose.

[0301] Other forms of administration include solutions or emulsions which may be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally, or intramuscularly and are prepared from sterile or sterilizable solutions. Pharmaceutical compositions of the present invention may be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, liquid or dusting powder.

[0302] An alternative means of transdermal administration is by use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin. The active ingredient can also be incorporated into an ointment consisting of a white wax or white soft paraffin base at a concentration of 1 to 10% by weight, together with such stabilizers and preservatives as may be required.

[0303] Injectable forms may contain 10 to 1000 mg, preferably 10 to 250 mg, of active ingredient per dose.

[0304] Compositions may be formulated in unit dosage form, ie, in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.

[0305] Dosage The dosage of the crystalline form of Compound (I) will depend on factors such as the patient's condition, body surface area, weight, and age. Suitable dosage levels are 10 mg (preferably 200 mg) per day to 700 mg (preferably 400 mg) per day. The crystalline form of Compound (I) can be administered as a single unit dosage, or, if desired, the dosage can be divided into convenient subunits to be administered one to several times throughout the day, depending on the patient's condition.

[0306] Those skilled in the art can easily determine the suitable dosage of one of the present compositions to be administered to a subject without unnecessary experimentation.Typically, a doctor will determine the actual dosage that will be most suitable for each patient, and this will depend on various factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of specific condition and the individual undergoing therapy.The dosage disclosed herein is an example of average case.Of course, there may be individual cases where higher or lower dosage ranges are appropriate, and these are also within the scope of the present invention.

[0307] The invention will now be further described with reference to the following figures. [Brief explanation of the drawings]

[0308] [Figure 1] FIG. 1 shows weight change (% db) versus relative humidity (%) for the monohydrochloride salt of Compound (I). [Figure 2]FIG. 1 is an isotherm plot for the monohydrochloride salt of Compound (I) showing % weight change (left axis) and % relative humidity (right axis) versus time (minutes) (horizontal axis) measured using a Hiden Isochema moisture sorption analyzer. [Figure 3] FIG. 1 shows an XRPD comparison of the monohydrochloride salt of Compound (I) (top trace), after GVS drying (middle trace) and after GVS 90% relative humidity (bottom trace). [Figure 4] Figure 1 shows DSC / TGA traces for the monohydrochloride salt of Compound (I), along with corresponding traces after GVS drying and after GVS 90% relative humidity. The DSC thermogram (bottom trace) was obtained using a PerkinElmer DSC 4000 at a heating rate of 20°C / min (peak maximum observed near 268°C). The top trace shows a TGA analysis of the same salt at a heating rate of 20°C / min using a PerkinElmer Pyris 1 TGA. [Figure 5] FIG. 1 shows the H NMR spectrum of the 1:2 L-malate salt of Compound (I). [Figure 6] 1 shows DSC and TGA thermographs for the 1:2 L-malate salt of Compound (I). The DSC thermogram (bottom trace) was obtained using a PerkinElmer DSC 4000 at a heating rate of 20° C. / min (peak maximum observed at 187.57° C.). The top trace shows a TGA analysis of the same salt using a PerkinElmer Pyris1 TGA at a heating rate of 20° C. / min. [Figure 7] FIG. 1 shows the DVS profile of the 1:2 L-malate salt of Compound (I), weight change (%) versus relative humidity (%). [Figure 8] FIG. 1 shows an XRPD comparison of the 1:2 L-malate salt of Compound (I) (top trace), after GVS drying (middle trace), and after GVS 90% relative humidity (bottom trace). [Figure 9] FIG. 1 shows the 1H NMR spectrum of the 1:2 succinate salt of Compound (I). [Figure 10] 1 shows DSC and TGA thermographs for the 1:2 succinate salt of Compound (I). The DSC thermogram (bottom trace) was obtained using a PerkinElmer DSC 4000 at a heating rate of 20° C. / min (peak maximum observed at 188.80° C.). The top trace shows a TGA analysis of the same salt using a PerkinElmer Pyris1 TGA at a heating rate of 20° C. / min. [Figure 11] FIG. 1 shows the DVS profile of the 1:2 succinate salt of Compound (I), weight change (%) versus relative humidity (%). [Figure 12] FIG. 1 shows an XRPD comparison of the 1:2 succinate salt of Compound (I) (top trace), after GVS drying (middle trace), and after GVS 90% relative humidity (bottom trace). [Figure 13] FIG. 1 shows the H NMR spectrum of the 1:2 maleate salt of compound (I). [Figure 14] 1 shows DSC and TGA thermographs for the 1:2 maleate salt of Compound (I). The DSC thermogram (bottom trace) was obtained using a PerkinElmer DSC 4000 at a heating rate of 20° C. / min (peak maximum observed at 203.80° C.). The top trace shows a TGA analysis of the same salt using a PerkinElmer Pyris1 TGA at a heating rate of 20° C. / min. [Figure 15] FIG. 1 shows the DVS profile of the 1:2 maleate salt of Compound (I), weight change (%) versus relative humidity (%). [Figure 16] FIG. 1 shows an XRPD comparison of the 1:2 maleate salt of Compound (I) (top trace), after GVS drying (middle trace), and after GVS 90% relative humidity (bottom trace). [Figure 17] FIG. 1 shows the H NMR spectrum of the monohydrobromide monohydrate salt of Compound (I). [Figure 18]1 shows DSC and TGA thermographs for the monohydrobromide monohydrate salt of Compound (I). The DSC thermogram (bottom trace) was obtained using a PerkinElmer DSC 4000 at a heating rate of 20° C. / min (peak maximum observed at 249.77° C.). The top trace shows a TGA analysis of the same salt using a PerkinElmer Pyris1 TGA at a heating rate of 20° C. / min. [Figure 19] FIG. 1 shows the DVS profile of the monohydrobromide monohydrate salt of Compound (I), weight change (%) versus relative humidity (%). [Figure 20] FIG. 1 shows an XRPD comparison of the monohydrobromide monohydrate salt of Compound (I) (top trace), after GVS drying (middle trace) and after GVS 90% relative humidity (bottom trace). [Figure 21] FIG. 1 shows the 1H NMR spectrum of the 1:1 p-toluenesulfonate salt of compound (I). [Figure 22] 1 shows DSC and TGA thermographs for the 1:1 p-toluenesulfonate salt of Compound (I). The DSC thermogram (bottom trace) was obtained using a PerkinElmer DSC 4000 at a heating rate of 20° C. / min (peak maximum observed at 238.99° C.). The top trace shows a TGA analysis of the same salt using a PerkinElmer Pyris 1 TGA at a heating rate of 20° C. / min. [Figure 23] FIG. 1 shows the DVS profile of the 1:1 p-toluenesulfonate salt of Compound (I), weight change (%) versus relative humidity (%). [Figure 24] FIG. 1 shows an XRPD comparison of the 1:1 p-toluenesulfonate salt of Compound (I) (top trace), after GVS drying (middle trace), and after GVS 90% relative humidity (bottom trace). [Figure 25] FIG. 1 shows the X-ray powder diffraction pattern of the monohydrochloride monohydrate salt of Compound (I). [Figure 26]FIG. 1 shows the X-ray powder diffraction pattern of the 1:2 L-malate salt of Compound (I). [Figure 27] FIG. 1 shows the X-ray powder diffraction pattern of the 1:2 succinate salt of Compound (I). [Figure 28] FIG. 1 shows the X-ray powder diffraction pattern of the 1:2 maleate salt of Compound (I). [Figure 29] FIG. 1 shows the X-ray powder diffraction pattern of the monohydrobromide monohydrate salt of Compound (I). [Figure 30] FIG. 1 shows the X-ray powder diffraction pattern of the 1:1 p-toluenesulfonate salt of Compound (I). [Figure 31] FIG. 1 shows the H NMR spectrum of the 1:1 monohydrochloride monohydrate salt of Compound (I).

[0309] The invention will now be further described with reference to the following non-limiting examples. [Example]

[0310] Abbreviation EtOH ethanol MeOH Methanol EtOAc ethyl acetate DCM dichloromethane t-BuOK Potassium tert-butoxide MeI methyl iodide RT room temperature Et2O diethyl ether NMP N-methylpyrrolidone HPLC High Performance Liquid Chromatography HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) DIPEA N,N-Diisopropylethylamine HOBt Hydroxybenzotriazole HRGC High Resolution Gas Chromatography KF Karl Fischer MeCN acetonitrile IMS Industrial Methylated Spirits TBME Methyl tert-butyl ether THF tetrahydrofuran MEK Methyl ethyl ketone nBuOAc n-Butyl acetate nPrOH n-propanol

[0311] 1. Equipment and Methods 1.1. Solution Proton NMR Using a JEOL EX 270MHz spectrometer equipped with an autosampler 1 H NMR spectrum Samples were collected. Samples were dissolved in appropriate deuterated solvents for analysis. Data were acquired using Delta NMR Processing and Control Software version 4.3.

[0312] 1.2.X-ray powder diffraction (XRPD) PANalytical diffractometer with Cu Kα radiation (45 kV, 40 mA) and θ-θ goniometer X-ray powder diffraction patterns were collected using a focusing mirror, a divergence slit (½”), Soller slits (4 mm) in both the incident and diverging beams, and a PIXcel detector. The software used for data collection was X'Pert Data Collector, version The data was presented using X'Pert Data Viewer, version 1.2d, using PANalytical's X'Pert PRO under ambient conditions via a transmission foil sample stage (polyimide-Kapton, 12.7 μm thick film). XRPD patterns were acquired over a period of 0.202004°s. -1The XRPD range was 2.994 to 35 degrees 2-theta at a continuous scan speed of 100 Hz. XRPD values ​​are given as degrees 2-theta ± 0.2 degrees 2-theta. The 2-theta values ​​in the accompanying tables are presented to four decimal places; in the accompanying claims, the 2-theta values ​​have been rounded to two decimal places. Those skilled in the art will understand that the 2-theta values ​​in the tables (which form the basis for the 2-theta values ​​in the claims) may be rounded to one decimal place.

[0313] 1.3. Differential Scanning Calorimetry (DSC) DSC data were collected on a PerkinElmer DSC4000 equipped with a 45-position sample holder. The instrument was verified for energy and temperature calibration using certified indium. A predetermined amount of sample, 0.5–3.0 mg, was placed in an aluminum pan with a pinhole and heated at 20°C for 1 min. -1 The mixture was heated to 30-300°C or varied as directed by the experimental method. -1 A purge of dry nitrogen was maintained over the sample. Pyris Software Instrument control, data acquisition and analysis were performed using v9.0.1.0203.

[0314] 1.4.Thermogravimetric analysis (TGA) TGA data were collected on a PerkinElmer Pyris 1 TGA equipped with a 20-position autosampler. The instrument was calibrated for temperature using certified weights and certified Alumel and Perkalloy. A predetermined amount of sample, 1-5 mg, was placed in a pre-tared aluminum crucible and heated at 20°C.min. -1 Heated from ambient temperature to 400°C. 20 ml min -1 A nitrogen purge was maintained over the sample. Instrument control, data acquisition and analysis were performed using Pyris Software v9.0.1.0203.

[0315] 1.5. Gravimetric Vapor Sorption (DVS) Hiden Isochema moisture sorption controlled by IGAsorp Systems Software V6.50.48 Sorption isotherms were obtained using an IGAsorp sorptor (model IGAsorp). The samples were heated at a constant temperature under instrument control. (25℃) 250ml.min -1 Humidity was controlled by mixing dry and humid nitrogen streams at a total flow rate of 1000 kJ / min. The instrument was validated for relative humidity content by measuring three calibrated Rotronic salt solutions (10-50-88%). Sample weight change was monitored as a function of humidity using a microbalance (accuracy + / - 0.005 mg). A defined amount of sample was placed in a tared mesh stainless steel basket under ambient conditions. The complete experimental cycle typically consisted of three scans (sorption, desorption, and sorption) at a constant temperature (25 °C) and 10% RH intervals over a 0-90% humidity range (60 min for each humidity level). This type of experiment should demonstrate the ability of the studied sample to absorb (or not absorb) moisture over a set of well-defined humidity ranges.

[0316] 1.6 High-resolution gas chromatography (HRGC) Agilent 6890 Series Gas Chromatograph equipped with a headspace sampler HRGC spectra were obtained by dissolving the sample in methanol.

[0317] 2. Preparation method for each salt The free base form of Compound (I) can be prepared according to the synthesis shown below in Schemes 1, 2 and 3 (methods described in WO 2009 / 040556; see also, in particular, compound

[0384] ):

[0318] [ka]

[0319] [ka]

[0320] [ka]

[0321] 2.1 Synthesis of Compound (I) (i) Intermediate A Stage 1

[0322] [ka]

[0323] Raney nickel catalyst (200 g, 50% water) was washed with EtOH (3 x 100 ml, solvent decanted). The catalyst was then suspended in ethanol (200 ml). To a suspension of Raney nickel (200 g, 50% suspension in EtOH) in EtOH (3 L) was added ethyl-1-cyanocyclopropanecarboxylate (600 g, 4.3119 mol). The hydrogenator was purged with N2 (3 x) and H2 (3 x). The reaction was pressurized with hydrogen to 20 bar and stirred overnight at room temperature. The mixture was filtered through a pad of Celite (500 g) and washed with ethanol (2 x 0.6 L). The filtrate was concentrated. The residue was dissolved in DCM (1.8 L), dried over MgSO, filtered, and concentrated to give the product as a clear oil (yield 580 g, 94%).

[0324] Stage 2

[0325] [ka]

[0326] To a solution of the amine from Stage 1 (800 g, 5.5874 mol) and cyclopentanone (520 mL, 5.867 mol) in DCM (8 L) was added NaBH(OAc) (1777 g, 8.381 mol) in portions over 1.5 h at room temperature. The reaction mixture was then stirred overnight at room temperature. To destroy excess reducing agent, a saturated solution of KCO in water (8 L) was added, and the reaction mixture was stirred at RT for 1 h (gas evolution, pH = 8). The layers were separated, and the aqueous layer was extracted with DCM (4 L). The combined organic layers were washed with KCO aqueous solution (4 L), dried over MgSO, filtered, and concentrated. This gave 1210.3 g of product as a clear oil (1157 g active (contained 4.3% DCM), 98% yield).

[0327] Stage 3

[0328] [ka]

[0329] A solution of 2,4-dichloro-5-nitropyrimidine (1309.4 g, 6.750 mol) in acetone (11.4 L) was cooled to 0-5°C and K2CO3 (933 g, 6.750 mol) was added. Then, a solution of the amine from Stage 2 (1426.3 g, 6.750 mol) in acetone (2.9 L) was added dropwise over 1.5 hours, maintaining the temperature below 5°C. After 1 hour, 1 H NMR analysis showed approximately 6% 2,4-dichloro-5-nitropyrimidine and no stage 2 amine. Stage 2 amine (86 g, 0.407 mol) in acetone (50 ml) was added and the mixture was stirred at RT for 1 h. The solid was filtered off and washed with acetone (1 L). The filtrate was concentrated at 25 °C (the product polymerizes at higher temperatures), and the residue was dissolved in DCM (8 L), washed with water (2 L), dried over MgSO, filtered, and concentrated at 25 °C. This gave the product as an orange oily solid (2755 g, LC purity 85%). The product was suspended in EtO (475 ml) and stirred at room temperature. The mixture was stirred for 15 minutes. Heptane (475 ml) was added, and the suspension was stirred at room temperature for 1 hour. After that time, the mixture was filtered, and the filter cake was washed with EtO / heptane (1:1, 2 x 950 ml) and dried in a vacuum oven at 25 °C overnight. This gave 1762.2 g of product as a yellow solid (71% yield, LC purity 96.99%).

[0330] Stage 4

[0331] [ka]

[0332] AcOH (7.6 L) was heated to 60 °C and the heating mantle was removed. Fe powder (431 g, 7.727 mol) was added portionwise over 15 min at 60 °C (no exotherm, slight gas evolution). The mixture was then cooled to 25 °C (ice bath), and the product from Stage 3 (950 g, 2.576 mol) was added portionwise over 3 h (a slight exotherm was observed, and cooling with ice / water maintained the reaction temperature at 25-30 °C). The reaction mixture was stirred overnight at 25 °C. After that time, an LC completion check indicated 82.0% product. The mixture was diluted with water (15.2 L, no exotherm), and the product was filtered off using a filter cloth. The filter cake was washed with water (500 ml) and then treated with saturated aqueous NaHCO3 (2 L, gas evolution). The solid was filtered off (filter paper) and washed with water (3 x 500 ml). The wet cake (1717 g) was combined with three batches of product from Stage 4 prepared by the same method [Batch 1 (950 g) - 1668 g wet, Batch 2 (950 g) - 1701 g wet, Batch 3 (581.1 g) 1113 g wet] and stirred in water (5 L) at room temperature for 1 hour. The solid was filtered off and dried in a vacuum oven at 50 °C for 5 days. This gave 2972.4 g of product as a brown solid (approximately 100% yield, LC purity 94.5%, KF 0.65%, contains Fe salts). The product was used in the next stage without purification.

[0333] Stage 5

[0334] [ka]

[0335] The product from Stage 4 (2019.1 g total, 1850.0 g active weight - assuming 100% yield in Stage 4) was added in portions over 10 minutes to a suspension of t-BuOK (854.3 g) in THF (19.0 L) within the specified range of 0-10 °C. The mixture was stirred for 30 minutes at a temperature between 0 and 10°C (final temperature 5.47°C), then methyl iodide (440 ml) was added dropwise over 23 minutes, maintaining the temperature within the specified temperature range of 0 to 5°C. The mixture was stirred within the specified temperature range of 0 to 5°C for 15 minutes, then warmed to 20°C over 2.5 hours, and then stirred within the specified temperature range of 20 to 25°C overnight (12 hours). HPLC analysis indicated the reaction was complete (0.5% product remaining from Stage 4, target <1.0% remaining). The salts were filtered off and washed with THF (1920 mL). The filtrate was concentrated in vacuo, and the residue (2321.2 g) was partitioned between DCM (5770 mL) and water (1150 mL). (Note: A cloudy aqueous layer was present; the residue did not completely dissolve before partitioning; this did not prevent the phases from separating.) The organic layer was dried over MgSO (426.2 g), filtered, washed with DCM (1000 mL), and concentrated in vacuo to give the product as a pale yellow solid (1924.3 g), which was oven-dried at 40° C. for 24 hours to give the product from Stage 5. Yield = (1502.2 g, 77.5%). HPLC purity of the material was 98.48% (0.0% product from Stage 4).

[0336] (ii) Intermediate D Stages 1' and 2'

[0337] [ka]

[0338] 4-Acetamidocyclohexanone (850 g, 5.477 mol), N-methylpiperazine (729 mL, 6.573 mol), and MeSO3H (28.5 mL, 0.438) in toluene (6.8 L) were heated at reflux using a Dean & Stark separator for 5 h (94 mL of water was collected). Those skilled in the art will recognize that alternative amine protecting groups, such as BOC, Bn2, and the like, can be used in compound XIII. After that time, the mixture was cooled to 50 °C (the mixture solidifies at lower temperatures) and diluted with EtOH (6.8 L). The intermediate enamine was treated in portions with NaBH4 (207.2 g, 5.477 mol) at 15–20 °C and stirred overnight at room temperature. Excess NaBH4 was destroyed with 6 M HCl (4 L) at 10–15 °C. Those skilled in the art will understand that alternative reducing agents, such as LiBH4 instead of NaBH4, can be used. The layers were separated, and the aqueous layer was treated with K2CO3 (1.2 kg, to achieve pH = 8). The solids were filtered off and washed with DCM (2.5 L, which was used later for extraction). The filtrate was concentrated. The residue was extracted with DCM (2 x 2.5 L), basified with 1.25 M KOH (200 ml, to pH = 10), and extracted with DCM (2.5 L). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product (1020 g) was combined with 3792 g of product from batches 1-3, prepared by the same method, and diluted with 50% heptane / DCM (16 L), 75% heptane / DCM (32 L), DCM (40 L), and then 10 L 1% MeOH / DCM. Purification with elution on basic alumina (16.5 kg) gave the product as a white solid (yield 2410 g, 47%; cis:trans ratio 36:64).

[0339] The product was combined with 753.7 g of the cis / trans product, dissolved in MeCN (9.32 L) at reflux, and allowed to cool slowly to RT overnight. The suspension was cooled to 5-10°C and stirred for 2 h. The precipitate was filtered off, washed with MeCN (1 x 3.1 L, 1 x 2 L, and 1 x 1 L) and sucked dry on the filter. The product was dried at 45°C overnight. This gave 544.9 g of product as a white solid (1613.2 g, ca. 25% yield).1 Greater than 95% purity by H NMR 1 1 H NMR showed no cis isomer).

[0340] Stage 3'

[0341] [ka]

[0342] Concentrated hydrochloric acid (4500 mL) was added to water (2240 ​​mL) over 5 minutes while maintaining the temperature within the specified range of 20-40°C (final temperature 23.83°C). Intermediate D acetate (1100.9 g) was added over 4 minutes, and then the reaction was heated to 105°C over 60 minutes. The reaction was heated at 95-106°C overnight (17.5 hours), by which time an in-process check by H NMR indicated the reaction was complete. The reaction mixture was cooled to within the specified range of 15-25°C over 72 minutes. Solid potassium hydroxide (5890.1 g) was added in portions over approximately 1 hour while maintaining the temperature within the specified range of 20-45°C to give a final pH of 12. The reaction mixture was cooled to within the specified range of 15-25°C over 5 minutes and stirred overnight (17.5 hours) within the specified range of 15-25°C (final temperature 17.97°C). The suspension was filtered and the filter cake was washed with THF (6120 mL x 3, then 4080 mL). The combined filtrate was returned to the vessel and the phases were separated. The organic phase was concentrated in vacuo in portions to give 1287.4 g of material. Residual water was removed by azeotroping with toluene (2025 mL, then 2020 mL). The product was then dissolved in DCM (2000 mL), the solid was filtered off (removing a small amount of inorganic material), washed with DCM (200 ml), and the filtrate was concentrated in vacuo. This gave the product as a low-melting solid (939.1 g, quantitative yield, active yield ( 1 1 H NMR) 888.4g, 97.9%). 1 4.59% toluene and 0.81% DCM by H NMR, 90.1% trans intermediate D by HRGC.

[0343] Alternative synthesis of intermediate D Alternatively, the reductive amination step can be carried out as follows:

[0344] [ka]

[0345] Boc-4-aminocyclohexanone (20 g, 93.8 mmol) was added to the flask at RT under N, followed by N-methylpiperazine (13 mL, 117.2 mmol), methanesulfonic acid (0.5 mL, 7.7 mmol), and toluene (140 mL). The slurry was heated to reflux in a Dean-Stark setup over 30 min [no exotherm observed upon warming] to produce a light brown solution. The solution was stirred at 110-115 °C for 6 h to remove HO, at which point 1 H NMR showed 83% enamine. The solution was cooled to 50 °C over 20 min (using an ice / water bath) and EtOH (100 mL) was added. The solution was then further cooled to 20 °C over 20 min and LiBH (2 M in THF, 100 mL, 200.0 mmol) was added dropwise over 30 min (an exotherm of 20-27 °C and significant off-gassing was observed). The reaction was stirred at RT for 18 h. At this point, 1H NMR showed less than 5% enamine. The reaction was quenched via the dropwise addition of 6 M HCl (approximately 150 mL, 900.0 mmol) over 15 min until a pH of 2 was observed [exotherm 20-25 °C and slight off-gassing]. The phases were separated and the organic layer was removed. The aqueous was then basified via the addition of K2CO3(s) (30 g, 217.1 mmol) over 15 min until a pH of 8 was reached [exotherm 20-28 °C and significant off-gassing]. The slurry was filtered and the filtrate reduced in vacuo to give a pale brown oil. The filter cake was washed with DCM (2 × 80 mL). The brown oil was partitioned between DCM from the filter cake washes and 2 M NaOH (20 mL). The aqueous was removed and extracted with DCM (90 mL). The combined DCM extracts were dried (MgSO4), filtered, and reduced in vacuo to give a pale orange oil. The oil was azeotroped with MeCN (100 mL) to give 23 g of a beige solid (82% crude yield). 1 H NMR indicated a trans to cis ratio of approximately 75 / 25 and an overall purity of approximately 50%. An 11 g portion of the solid was slurried in MeCN (55 mL), heated to 70° C. (a solution formed at 67° C.), and then cooled to RT over 1 h. The slurry was stirred at RT for 18 h. The slurry was filtered, washed (MeCN, 5 mL), and dried in vacuo to give the product with less than 1% cis. 1 This gave 4.3 g of the trans Boc-protected product (32% yield) as a white powder with 95% purity by 1 H NMR.

[0346] The trans Boc-protected product was then deprotected to yield intermediate D by treatment with concentrated HCl under the same conditions described above.

[0347] Final Compound (I) Synthesis Stage Stage 6 (Intermediate C)

[0348] [ka]

[0349] A solution of the product from Stage 5 (Intermediate A) (1490.6 g active, 1492.7 g total) and amino acid (898.9 g) in NMP (2960 mL) was heated within the specified range of 115-125°C over 51 minutes, then heated within the range of 115-125°C for 36 hours. The batch was cooled with stirring for 4 hours, after which time it was allowed to cool without stirring (when cooled, the batch contains a significant amount of solids that do not easily stir). After standing for approximately 29 hours, the batch was warmed to 52°C, allowing the batch to be sampled as a mobile, homogeneous suspension. Analysis by HPLC indicated the reaction was complete (83.35% product from Stage 6 present, target GT 75%). The batch was cooled to 20°C, and the mixture was diluted with water for pouring (6000 mL). A moderate exotherm was observed, causing the batch to warm to 26.8°C. External cooling was applied, and the batch was then stirred for 40 minutes within the specified range of 10-25°C. The product was filtered, washed with water for pouring (2 x 1500 mL), suction dried, and oven-dried within the specified range of 45-55°C for 18-20 hours, by which time the product in each of the three oven-drying trays showed a water content of 10% (by KF analysis). To remove unreacted product from Stage 5, the crude product (2212.7 g) was slurried in toluene (6630 mL) for 74 minutes at 10-25°C (final temperature 18.3°C). The solid was filtered, washed with toluene (1520 mL), and oven-dried for 17 hours within the specified range of 45-55°C. In-process analysis of the solids in each of the three oven-dried trays by HPLC was 0.21-0.35% product from stage 5 (target LT 0.5%); 1 H NMR showed 1.56-1.85% NMP (target NMT 2.5%), and toluene 1 No H NMR was detected (Result FOI). The solid was then packaged. Yield 1905.8 g (89.7% yield). Purity by HPLC 93.16% (0.30% Stage 5).

[0350] Stage 7

[0351]

change

[0352] To a suspension of the product from Stage 6 (1869.8 g active, 1896.5 g total) in DCM (18,640 mL) was added HBTU (1801.9 g), rinsing with DCM (20 mL) within the specified range of 15-25 °C. DIPEA (1500 mL) was then added dropwise within the specified range of 15-25 °C. The reaction mixture was stirred within the specified range of 15-25 °C for 31 minutes, by which time analysis by TLC indicated complete consumption of the product from Stage 6. Intermediate D (905.1 g) was added in portions over 30 minutes, while maintaining the temperature within the specified range of 15-25 °C. The reaction mixture was stirred within the specified range of 15-25 °C for 69 minutes. The batch was then sampled, and analysis by HPLC indicated 0.02% product remaining from Stage 6 (target LT 0.5%). To remove HOBt, the mixture was washed with NaOH solution (9440 mL, then 9400 mL, then 9420 mL, 0.4 M NaOH) and water (9400 mL). After the final wash, in-process analysis showed 0.05% HOBt by HPLC (target LT 1%). It was noted that a significant amount of solid had precipitated in the organic layer. The organic layer could not be immediately dried with MgSO because solid would have been lost during filtration. The suspension in the organic phase was filtered, and the filter cake was washed with DCM (500 mL). The filtrate was then dried with MgSO (1284.3 g), filtered, and washed with DCM (1500 mL). The organics were then concentrated in vacuo at 40 °C. The filtered solids were then added to give 3489.9 g of solid. The crude product (in six flasks) was evaporated from EtOAc (6500 mL total). The product was returned to the 50 L vessel, slurried in 8500 mL of EtOAc within the specified range of 10-25°C for 36 minutes, filtered, washed with 2160 mL, then 2150 mL of EtOAc, and dried within the specified range of 45-55°C for 64.5 hours. This gave 2475.3 g of product (0% EtOAc, 10.6% DCM by H NMR). The product was dissolved in 5980 mL of MeOH within the specified range of 60-70°C (final temperature 62.7°C). The solution was immediately polish-filtered into the 50 L vessel (final temperature 54.17°C). The solution was warmed within the specified range of 60-70°C (final temperature 60.3°C).Water for injection (5760 mL) was added dropwise over 39 minutes while maintaining the temperature within the specified range of 60-70 °C. The mixture was stirred within the specified range of 60-70 °C for 10 minutes and then cooled to 25 °C over 123 minutes. After stirring within the specified range of 15-25 °C for 21 minutes (final temperature 19.16 °C), the suspension was filtered, washed with a 1:1 solution of MeOH in water for injection (2880 mL, then 2700 mL), sucked dry on the filter, and oven-dried within the specified range of 45-55 °C for 19.5 hours to give 2076.3 g (78.8% yield) of product. Purity by HPLC: 96.43% (0.33% product cis from Stage 7, 0.01% product from Stage 6, 0.01% HOBt, spec. NLT 95.0%); 2.75% water by KF.

[0353] 2.2 Monohydrochloric acid monohydrate

[0354] [ka]

[0355] Final salt production began with 2033.6 g active weight (2067.3 g total). The batch crystallized from the HCl / ethanol / ethyl acetate mixture as expected, and post-filtration XRPD analysis of the filter cake showed the crystalline morphology as per Table 1. The product was dried for 5 days to remove the solvent and then equilibrated for 1 day to achieve the required water content. The product was obtained in 84.8% yield (target 86%), and the product was within the required purity.

[0356] A suspension of free base Compound (I) (2033.6 g active, 2067.3 g total) in filtered ethanol (14,240 mL) was heated to 75°C over 55 minutes. After stirring within the specified range of 75-85°C for 30 minutes (final temperature 77.26°C), the mixture was then cooled to within the specified range of 65-75°C over 5 minutes (final temperature 74.98°C). Filtered 1.25 M HCl in EtOH (2,640 mL) was added over 16 minutes while maintaining the temperature within the specified range of 65-75°C, followed by stirring within the specified range for 10 minutes (final temperature 69.83°C). Filtered EtOAc (20,500 mL) was charged over 50 minutes while maintaining the temperature within the specified range of 50-70°C. After stirring for 10 minutes within the specified range of 50-70°C, the mixture was cooled within the specified range of 15-25°C over 2 hours and then stirred within the specified range of 15-25°C for 12.5 hours (final temperature 19.62°C). The suspension was cooled within the specified range of 0-10°C and stirred for 3 hours (final temperature 5.00°C). The suspension was filtered and washed with polished filtered ethyl acetate (2000 mL). Analysis showed the crystalline form as per Table 1. The solid was oven-dried within the specified temperature range of 45-55°C for 5 days to remove the solvent (mass 1834.5 g). The oven was turned off and filtered air (1.2 μm filter size) was pulled into the oven for 25 hours to equilibrate (absorb moisture), giving 1875.5 g of product as an off-white solid. Purity 97.22% by HPLC; 3.29% water by KF; 1878 ppm ethyl acetate and 689 ppm ethanol by HRGC.

[0357] 2.3 L-Malate 2:1 Succinate 2:1, Maleic Acid (Maleate) 2:1, a common method used for monohydrochloride monohydrate and monobromide monohydrate order A 4.297 ml solution of 0.5 g of Compound (I) in ethanol was charged to a reaction tube, suspended with stirring, and heated to 75°C. A counterion solution (e.g., HCl, HBr, L-malic acid, maleic acid, succinic acid) in ethanol or an ethanol / THF mixture, equal to the required equivalents of Compound (I), was charged to the API solution, and the mixture was stirred and controlled to cool from 75°C to 60°C to ambient temperature, held for approximately 2 hours, then cooled to 40°C and held for approximately 2 hours. The counterion equivalents (volume (ml) and concentration (mg / ml)) are listed in Table 7. The procedure can be adapted to add EtOAc as an antisolvent before the cooling step, which can increase the yield. The mixture was then cooled to ambient temperature. The mixture was cooled to 50°C and stirred at ambient temperature for approximately 18 hours. The solids were isolated by filtration and dried in vacuo at 50°C for approximately 20 hours. Observations of the mixture at various temperatures are detailed in Table 7. Recovery and appearance of the solids are detailed in Table 8.

[0358] All salt forms have sharp melting points and are highly crystalline as judged by XRPD. The monohydrochloride monohydrate was a stable crystalline form with relatively low hygroscopicity.

[0359] The presently claimed forms are characterized as slightly hygroscopic as defined by the classification in Table 9 (Hygroscopicity Classification (adapted from Ph. Eur. and Sihorkar et al, Pharmaceutical Dev. & Technol. (2013), 18(2), 348-358) and sorption data obtained from GVS analysis over the range of 40-80% RH at 25°C (Table 10). In contrast, other salts (e.g., 1:1 citrate and 1:0.5 L-tartrate) were characterized as hygroscopic using the same classification.

[0360] 2.4 p-Toluenesulfonate 0.5 g of Compound (I) was dissolved in THF (7.5 ml) and ethanol (1 ml) with stirring and heated to 60°C. 1.0 equivalent of p-toluenesulfonic acid was added as a 358.52 mg / ml solution in 0.430 ml of ethanol, and the mixture was cooled to ambient temperature. The clear solution was then concentrated under ambient conditions with stirring for approximately 90 hours without significant loss of solvent or evidence of crystallization. The volume of the reaction mixture was reduced by approximately one-quarter with a nitrogen stream, which yielded a thick white suspension after approximately 3 hours of stirring. 4 x 0.5 ml of ethanol was then added to the mixture to improve its fluidity, and the mixture was allowed to equilibrate at ambient temperature for approximately 21 hours. The solid was isolated by filtration and dried in vacuo at 50°C for approximately 19 hours. The recovery and appearance of the solid are detailed in Table 8.

[0361] Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention that are obvious to those skilled in the relevant fields are intended to be within the scope of the claims.

[0362] [Table 1]

[0363] [Table 2]

[0364] [Table 3]

[0365] [Table 4]

[0366] Table 5

[0367] Table 6

[0368] Table 7

[0369] Table 8

[0370] Table 9

[0371] Table 10

Claims

1. Compound (I) in the form of a pharmaceutically acceptable salt, or a solvate or co-crystal of said pharmaceutically acceptable salt. 【Chemistry 1】 wherein the crystalline form is monohydrochloride monohydrate.

2. 5.57±0.2, 6.19±0.2, 7.97±0.2, 8.32±0.2, 10.48±0.2, 10.72±0.2, 11.83±0.2, 12.53±0.2, 12.74±0.2, 13.34±0.2, 13.86±0.2, 14.69±0.2, 15.62±0.2, 16.02±0.2, 16.75±0.2, 17.02±0.2, 17.42±0.2, 18.19±0.2, 18.81±0.2, 19.08±0.2, 19.49±0.2, 19.83±0.2, 20.15±0.2, 20.55±0.2, 21 2. The crystalline form of claim 1, characterized by an X-ray powder diffraction pattern having two or more diffraction peaks at 2[theta] values ​​selected from: 22.82±0.2, 23.78±0.2, 24.68±0.2, 25.10±0.2, 25.70±0.2, 25.86±0.2, 26.86±0.2, 27.92±0.2, 28.53±0.2, 28.92±0.2, 29.71±0.2, 30.80±0.2, 31.56±0.2, 32.38±0.2, 32.98±0.2, and 34.13±0.

2.

3. 5.57±0.2, 6.19±0.2, 7.97±0.2, 8.32±0.2, 10.48±0.2, 10.72±0.2, 11.83±0.2, 12.53±0.2, 12.74±0.2, 13.34±0.2, 13.86±0.2, 14.69±0.2, 15.62±0.2, 16.02±0.2, 16.75±0.2, 17.02±0.2, 17.42±0.2, 18.19±0.2, 18.81±0.2, 19.08±0.2, 19.49±0.2, 19.83±0.2, 20.15±0.2, 20.55±0.2, 21 3. The crystalline form of claim 2, characterized by an X-ray powder diffraction pattern having three or more diffraction peaks at 2[theta] values ​​selected from: 22.82±0.2, 23.78±0.2, 24.68±0.2, 25.10±0.2, 25.70±0.2, 25.86±0.2, 26.86±0.2, 27.92±0.2, 28.53±0.2, 28.92±0.2, 29.71±0.2, 30.80±0.2, 31.56±0.2, 32.38±0.2, 32.98±0.2, and 34.13±0.

2.

4. 5.57±0.2, 6.19±0.2, 7.97±0.2, 8.32±0.2, 10.48±0.2, 10.72±0.2, 11.83±0.2, 12.53±0.2, 12.74±0.2, 13.34±0.2, 13.86±0.2, 14.69±0.2, 15.62±0.2, 16.02±0.2, 16.75±0.2, 17.02±0.2, 17.42±0.2, 18.19±0.2, 18.81±0.2, 19.08±0.2, 19.49±0.2, 19.83±0.2, 20.15±0.2, 20.55±0.2, 21 3. The crystalline form of claim 2, characterized by an X-ray powder diffraction pattern having four or five or more diffraction peaks at 2[theta] values ​​selected from: 22.12±0.2, 22.82±0.2, 23.78±0.2, 24.68±0.2, 25.10±0.2, 25.70±0.2, 25.86±0.2, 26.86±0.2, 27.92±0.2, 28.53±0.2, 28.92±0.2, 29.71±0.2, 30.80±0.2, 31.56±0.2, 32.38±0.2, 32.98±0.2, and 34.13±0.

2.

5. 5.57±0.2, 6.19±0.2, 7.97±0.2, 8.32±0.2, 10.48±0.2, 10.72±0.2, 11.83±0.2, 12.53±0.2, 12.74±0.2, 13.34±0.2, 13.86±0.2, 14.69±0.2, 15.62±0.2, 16.02±0.2, 16.75±0.2, 17.02±0.2, 17.42±0.2, 18.19±0.2, 18.81±0.2, 19.08±0.2, 19.49±0.2, 19.83±0.2, 20.15±0.2, 20.55±0.2, 21 3. The crystalline form of claim 2, characterized by an X-ray powder diffraction pattern having five or six or more diffraction peaks at 2[theta] values ​​selected from: 22.82±0.2, 23.78±0.2, 24.68±0.2, 25.10±0.2, 25.70±0.2, 25.86±0.2, 26.86±0.2, 27.92±0.2, 28.53±0.2, 28.92±0.2, 29.71±0.2, 30.80±0.2, 31.56±0.2, 32.38±0.2, 32.98±0.2, and 34.13±0.

2.

6. 5.57±0.2, 6.19±0.2, 7.97±0.2, 8.32±0.2, 10.48±0.2, 10.72±0.2, 11.83±0.2, 12.53±0.2, 12.74±0.2, 13.34±0.2, 13.86±0.2, 14.69±0.2, 15.62±0.2, 16.02±0.2, 16.75±0.2, 17.02±0.2, 17.42±0.2, 18.19±0.2, 18.81±0.2, 19.08±0.2, 19.49±0.2, 19.83±0.2, 20.15±0.2, 20.55±0.2, 21 3. The crystalline form of claim 2, characterized by an X-ray powder diffraction pattern having 6 or 7 or more diffraction peaks at 2[theta] values ​​selected from: 22.12±0.2, 22.82±0.2, 23.78±0.2, 24.68±0.2, 25.10±0.2, 25.70±0.2, 25.86±0.2, 26.86±0.2, 27.92±0.2, 28.53±0.2, 28.92±0.2, 29.71±0.2, 30.80±0.2, 31.56±0.2, 32.38±0.2, 32.98±0.2, and 34.13±0.

2.

7. 3. The crystalline form of claim 1 or 2, wherein the X-ray powder diffraction pattern comprises two or more diffraction peaks at 2[theta] values ​​selected from 8.32±0.2, 10.48±0.2, 11.83±0.2, 12.53±0.2, 16.02±0.2, 16.75±0.2, 18.19±0.2, 18.81±0.2, 19.49±0.2, 20.55±0.2, and 25.70±0.

2.

8. 8. The crystalline form of claim 7, characterized by an X-ray powder diffraction pattern having three, four, or five diffraction peaks at 2[theta] values ​​selected from 8.32±0.2, 10.48±0.2, 11.83±0.2, 12.53±0.2, 16.02±0.2, 16.75±0.2, 18.19±0.2, 18.81±0.2, 19.49±0.2, 20.55±0.2, and 25.70±0.

2.

9. 8. The crystalline form of claim 7, characterized by an X-ray powder diffraction pattern having 6, 7, 8, 9, or 10 diffraction peaks at 2[theta] values ​​selected from 8.32±0.2, 10.48±0.2, 11.83±0.2, 12.53±0.2, 16.02±0.2, 16.75±0.2, 18.19±0.2, 18.81±0.2, 19.49±0.2, 20.55±0.2, and 25.70±0.

2.

10. 10. The crystalline form of any of claims 1 to 9, characterized by an X-ray powder diffraction pattern in which the peak positions match those of the pattern shown in Figure 25.

11. 11. The crystalline form of any of claims 1 to 10, characterized by a differential scanning calorimetry trace recorded at a heating rate of 20°C per minute, exhibiting a maximum endothermic peak at a temperature of about 265°C to about 275°C.

12. 12. The crystalline form of any of claims 1 to 11, characterized by a differential scanning calorimetry trace consistent with that shown in Figure 4.

13. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 12 and a pharmaceutically acceptable carrier, diluent or excipient.

14. A crystalline form according to any one of claims 1 to 12 for use in medicine.

15. 13. The crystalline form of any of claims 1 to 12 for use in the prevention or treatment of a proliferative disorder, an immune-mediated or inflammatory disorder, an autoimmune or autoimmune-mediated disorder, a renal disorder or a viral disorder.

16. 10. A process for preparing the crystalline form of claim 1, comprising: (i) preparing a mixture comprising compound (I) and ethanol and heating the mixture to at least about 70°C; (ii) preparing a solution of hydrochloric acid in ethanol or ethanol / THF and charging it to the mixture produced in step (i), and optionally adding ethyl acetate as an antisolvent to the mixture thus produced; (iii) gradually cooling the mixture produced in step (ii) to ambient temperature; (iv) isolating said crystalline form from said mixture; The method comprising:

17. Step (iii) (a) cooling the mixture produced in step (ii) to about 60°C with stirring and holding at about 60°C for at least 1 hour; (b) cooling the mixture from step (a) to about 40°C while stirring and holding at about 40°C for at least 1 hour; (c) cooling the mixture from step (b) to ambient temperature and stirring at ambient temperature for at least 12 hours; 17. The method of claim 16, comprising:

18. 18. A crystalline form obtained or obtainable by the method of claim 16 or 17.

19. 14. A method for preparing the pharmaceutical composition of claim 13, comprising the step of admixing the crystalline form of any of claims 1 to 12 with a pharmaceutically acceptable diluent, excipient or carrier.

20. 13. Use of the crystalline form of any of claims 1 to 12 in the preparation of another solid state form of compound (I) or a salt thereof or a co-crystal thereof.

21. 13. A method for preparing another solid state form of compound (I) or a salt or co-crystal thereof, said method comprising the steps of preparing a crystalline form according to any of claims 1 to 12 and converting it into another solid state form of compound (I) or a salt or co-crystal thereof.

22. Use of the crystalline form according to any one of claims 1 to 12 in the preparation of a pharmaceutical composition.

23. 10. A method for preparing a crystalline salt form of compound (I) as defined in claim 1, comprising treating a solution or suspension of the free base form of compound (I) with HCl and crystallizing the product so produced.

24. 24. The process of claim 23, carried out in ethanol or a mixture of ethanol and THF.

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