EA044028B1 - JAK INHIBITORY COMPOUND XYNAFOATE SALT - Google Patents

Description

BACKGROUND OF THE INVENTION

The novel salt of formula (I) of the present invention is expected to be useful for the treatment or prevention of conditions mediated in whole or in part by Janus kinases (or JAKs), which are a family of cytoplasmic protein tyrosine kinases including JAK1, JAK2, JAK3 and TYK2. Each JAK kinase is selective for specific cytokine receptors, although several JAK kinases can interact with specific cytokine or signaling pathways. Studies indicate that JAK3 binds to the common gamma chain (yc) of various cytokine receptors. In particular, JAK3 selectively binds to receptors and is part of the signaling pathway for the cytokines IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. JAK1 kinase interacts with the cytokine receptors IL-2, IL-4, IL-7, IL-9 and IL-21, among others. When certain cytokines bind to their receptors (e.g., IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), the receptors oligomerize, causing the cytoplasmic tails of the associated JAK kinases to become at close range and promote trans-phosphorylation of tyrosine residues of the JAK kinase. This trans-phosphorylation leads to activation of JAK kinase.

Phosphorylated JAK kinases bind to various signal transducers and activators of transcription (STAT) proteins. Such STAT proteins, which are DNA-binding proteins activated by phosphorylation of tyrosine residues, function as both signaling molecules and transcription factors, and ultimately bind to specific DNA sequences present in the promoters of cytokine-responsive genes (Leonard et al (2000), J. Allergy Clin. Immunol. 105:877-888). JAK/STAT signaling has been implicated in mediating many types of abnormal immune responses such as allergies, asthma, autoimmune diseases such as allograft rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid malignancies and types hematological malignancies such as leukemia and lymphomas. For a review regarding pharmaceutical interference with the JAK/STAT signaling pathway, see Frank, (1999), Mol. Med. 5:432:456, and Seidel et al. (2000), Oncogene 19:2645-2656, and Vijayakriishnan et al., Trends Pharmacol. Sci 2011, 32, 25-34, and Flanagan et al., J. Med. Chem.2014, 57, 5023-5038.

Given the importance of JAK kinases, compounds that modulate the JAK signaling pathway may be useful for the treatment of diseases or conditions that are associated with the functioning of lymphocytes, macrophages or mast cells (Kudlacz et al. (2004) Am. J. Transplant 4:51-57 ; Changelian (2003) Science 302:875-878). Conditions for which the therapeutic utility of targeting JAK signaling or modulating JAK kinases is being considered include leukemia, lymphoma, graft rejection (eg, pancreatic islet cell graft rejection, applications related to bone marrow transplantation (eg, graft-versus-host disease) , autoimmune diseases (eg diabetes) and inflammation (eg asthma, allergic reactions).

Given the variety of conditions expected to benefit from treatments that modulate the JAK signaling pathway, it is clear that new compounds and new forms of compounds that modulate the JAK signaling pathway and methods of administering such compounds should provide significant therapeutic benefits to a wide range of patients.

Short description

The present invention relates to new salts of formula (I)

pharmaceutical compositions containing salts of formula (I), and methods of their use.

The compounds of formula (I) are described in international patent application PCT/EP 2018/051038, which discloses a class of JAK inhibitory compounds including (R)-N-(3-(5-fluoro-2-((2-fluoro-3( methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1yl)propanamide - see example 35. In international patent application PCT/EP 2018 /051038 additional JAK inhibitory compounds are described, including various salts of (R)-N-(3-(5-fluoro-2-((2-fluoro-3(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H -indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1yl)propanamide.

The compounds of formula (I) disclosed herein are compounds prepared as novel salts that are useful in the treatment of conditions that involve targeting the JAK signaling pathway or inhibiting JAK kinases, particularly JAK1.

In at least one embodiment, the present invention provides compounds of formula (I) obtained as a xinafoate (1-hydroxy-2-naphthoate) salt (formula (Ia))

4-{(2R)-1-[(3-{5-fluoro-2-[2-fluoro-3-(methanesulfonyl)anilino]pyrimidin-4-yl}-1H-indol-7yl)amino]-3- methoxy-1-oxopropan-2-yl}-1-methylpiperazin-1-ium 1-hydroxynaphthalene-2-carboxylate.

The xinafoate salt of the present invention is characterized by a 1:1 xinafoic acid stoichiometry (as shown above). Also disclosed herein is a process for preparing the xinafoate salt of formula (Ia). Also disclosed are pharmaceutical compositions containing the xinafoate salt of formula (Ia) and a pharmaceutically acceptable diluent, excipient or carrier. In another embodiment, methods are disclosed for treating a JAK-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a xinafoate salt of formula (Ia). In another embodiment, a xinafoate salt of formula (Ia) is disclosed for use in the treatment of a disorder associated with JAK. In another embodiment, pharmaceutical compositions are disclosed containing a xinafoate salt of formula (Ia) for use in the treatment of a disorder associated with JAK. In another embodiment, the use of a xinafoate salt of formula (Ia) in the manufacture of a medicament for the treatment of a disorder associated with JAK is disclosed. Also disclosed is a new process for preparing the xinafoate salt of formula (Ia) and two new intermediates:

4-[(1R)-1-carboxy-2-methoxyethyl]-1-methylpiperazin-1-ium (2R,3R)-3-carboxy-2,3 dihydroxypropanoate hydrate (1:1:2), as illustrated below

and 1-[(1R)-1-carboxy-2-methoxyethyl]-4-methylpiperazine-1,4-diium dichloride, as illustrated below

Description of the figures

Shown is an X-ray powder diffraction (XRPD) pattern for 4-{(2R)-1-[(3-{5fluoro-2-[2-fluoro-3-(methanesulfonyl)anilino]pyrimidin-4-yl}-1H-indole -7-yl)amino]-3-methoxy-1oxopropan-2-yl}-1-methylpiperazin-1-ium 1-hydroxynaphthalene-2-carboxylate.

Detailed description

In some embodiments, solid forms of the compounds of formula (I) and (Ia) are disclosed herein. The term solid form includes polymorphs, crystalline salts, solvates, hydrates and amorphous forms of the compounds of formula (I) and (Ia). According to at least one embodiment of the present invention, the salts of the present invention are crystalline. Salts may also be in solvated or non-solvated forms, such as, for example, hydrated forms. It should be understood that the present invention covers all such solvated and non-solvated forms of the compounds of formula (I). The term solvate refers to crystal structures of the same chemical substance that contain solvent molecules within the molecular packing of the crystal structure. The term hydrates refers to crystalline structures of the same chemical substance that contain water molecules in a molecular packing of the crystalline structure.

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Compounds can occur in different forms of crystal structure, known as polymorphs. As used herein, the term polymorph means a crystalline form having the same chemical composition but a different spatial arrangement of the molecules, atoms and/or ions that form the crystal. Although polymorphs have the same chemical composition, they may have different geometric configurations, and hence they may exhibit different physical properties such as density, hardness, melting point, rigidity, durability, stability, solubility, etc.

It is well known that the characteristics of solids can be determined using traditional techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), diffuse reflectance Fourier transform (DRIFT), near-field spectroscopy infrared (NIR), liquid and/or solid-state nuclear magnetic resonance spectroscopy. The water content of such solids can be determined using Karl Fischer analysis.

The solid forms described herein provide substantially the same XRPD patterns as the XRPD patterns shown in the figures and are characterized by the different 2-theta (2θ) angle values shown in the tables included herein. One skilled in the art will appreciate that it is possible to obtain an XRPD pattern or diffraction pattern that is characterized by one or more measurement uncertainty values depending on the recording conditions of the measurements, such as the equipment or instrument used. Likewise, it is common knowledge that intensity values in an XRPD pattern can fluctuate depending on measurement conditions or sample acquisition based on preferred orientation. XRPD practitioners will further appreciate that the relative intensity of the peaks can also be affected by, for example, grains larger than 30 µm and non-uniform aspect ratios. One skilled in the art will appreciate that the position of the reflections can be affected by the exact height at which the sample is placed in the diffractometer, as well as the zero calibration of the diffractometer. The flatness of the sample surface may also have a minor influence.

For these reasons, the diffraction pattern data provided should not be regarded as absolute values (Jenkins, R & Snyder, R.L. 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London ; Klug, H. P. & Alexander, L. E. (1974), 'X-Ray Diffraction Procedures'). It should also be understood that the solid forms included herein are not limited to those that provide XRPD radiographs identical to the XRPD radiographs shown in the figures, nor are any solid forms that provide XRPD radiographs substantially the same as the radiographs shown in the figures are within the scope of the corresponding embodiment. One skilled in the art of XRPD is able to conclude that the XRPD radiographs are substantially identical. Typically, XRPD diffraction angle measurement uncertainty is approximately 2θ (±0.2°), and this level of measurement uncertainty should be taken into account when analyzing the powder X-ray diffraction pattern in the figures and when reading the data contained in the tables included herein.

Form A.

In at least one embodiment, Form A is disclosed, which is the xinafoate salt of 4-{(2R)-1-[(3-{5-fluoro-2-[2-fluoro-3-(methanesulfonyl)anilino]pyrimidine-4 -yl}-1Nindol-7-yl)amino]-3-methoxy-1-oxopropan-2-yl}-1-methylpiperazin-1-ium 1-hydroxynaphthalene-2-carboxylate.

In some embodiments, Form A is characterized in that it provides an X-ray powder diffraction (XRPD) pattern as shown in FIG. 1.

In some embodiments, Form A is characterized by an XRPD pattern containing at least one peak, expressed in degrees 2-theta (±2°), selected from the peaks listed in table. 1. It will be appreciated that the 2-theta angle values of a powder X-ray diffraction pattern may vary slightly from one device to another or from one sample to another, and therefore the values given should not be considered absolute.

In some embodiments, Form A is characterized in that it provides at least one of the following 2θ angle values measured using CuKa radiation: 15.0° and 21.0° and 22.6°.

In some embodiments, Form A is characterized in that it provides at least one of the following 2θ angle values measured using CuKa radiation: 8.2, 8.9, 11.2, 14.2, 15.0, 15. 3, 16.2, 17.5, 21.0, 22.6, 23.0, 23.7, 24.6 and 26.2°.

In some embodiments, the degree of crystallinity of Form A is greater than about 60%, such as greater than about 80%, such as greater than about 90%, and in at least one embodiment greater than about 95%. In yet another embodiment, the degree of crystallinity is greater than about 98%.

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According to a further aspect of the present invention, there is provided a method for preparing Form A, comprising:

(i) dissolving 5-((5-methyl-2-((3,4,5-trimethylphenyl)amino)pyrimidin-4-yl)amino)benzo[d]oxazol-2(3H)-one in free base form in a suitable solvent such as DMSO;

(ii) dissolving xinafoic acid in a suitable solvent such as DMSO;

(iii) mixing the two solutions;

(iv) optionally adding seed crystals of 5-((5-methyl-2-((3,4,5trimethylphenyl)amino)pyrimidin-4-yl)amino)benzo[d]oxazol-2(3H)-one xinafoate salt;

(v) allowing crystallization of the xinafoate salt of 5-((5-methyl-2-((3,4,5-trimethylphenyl)amino)pyrimidin-4-yl)amino)benzo[d]oxazol-2(3H)-one and (vi) isolating the xinafoate salt of 5-((5-methyl-2-((3,4,5-trimethylphenyl)amino)pyrimidin-4yl)amino)benzo[d]oxazol-2(3H)-one. In accordance with a further aspect of the present invention, there is provided a method for preparing two new intermediates, which are 4-[(1R)-1-carboxy-2-methoxyethyl]-1-methylpiperazin-1-ium (2R,3R)-3-carboxy hydrate -2,3dihydroxypropanoate (1:1:2) and 1-[(1R)-1-carboxy-2-methoxyethyl]-4-methylpiperazine-1,4diium dichloride, including:

(i) dissolving lithium 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate in distilled water at pH 4;

(ii) dissolving L-(+)-tartaric acid in distilled water;

(iii) mixing the two solutions from step (i) and step (ii) in a suitable solvent such as ethanol to initiate crystallization;

(iv) stirring the mixture from step (iii) for 20 hours at room temperature;

(v) adding a suitable solvent to the mixture from step (iv), such as ethanol, and cooling before performing filtration to obtain the product being 4-[(1R)-1carboxy-2-methoxyethyl]-1-methylpiperazine-1-hydrate ia (2R,3R)-3-carboxy-2,3-dihydroxypropanoate (1:1:2);

(vi) collecting the product of step (v) and drying for 72 hours under reduced pressure;

(vii) dissolving the product of step (vi) in distilled water;

(viii) performing a cation exchange on the product of step (vii) and (ix) eluting the product of step (viii) with 2 M HCl and evaporating this solution to dryness, which initiates the crystallization of 1-[(III)-1- dichloride carboxy-2-methoxyethyl]-4methylpiperazine-1,4-diium.

Pharmaceutical compositions and methods of use

The new salts presented herein can be administered by inhalation as micronized solids without any additional excipients, diluents or carriers. In at least one embodiment, pharmaceutical compositions are disclosed comprising Form A in combination with a pharmaceutically acceptable diluent or carrier.

The compositions of the present invention may be presented in a form suitable for administration by inhalation (eg, as a fine powder or liquid aerosol) or for administration by insufflation (eg, as a fine powder) using a suitable device.

The compositions of the present invention can be prepared by conventional procedures using conventional pharmaceutical excipients well known in the art. For example, compositions intended for inhalation may contain, for example, micronized lactose or other suitable excipients in an amount of not more than 90% w/w. compositions.

If required, new salts can be ground or micronized prior to formulation to ensure uniform particle size distribution. For example, Form A can be milled to provide an average particle size of from about 1 to 3 microns. Suitable grinding and micronization methods are generally known. (Midoux et al. (1999), Powder Technology, 104:113 -120).

Form A of the present invention is expected to be useful in the treatment of diseases or medical conditions mediated in whole or in part by JAKs, in particular JAK1, i.e. Form A can be used to obtain the effect of inhibiting JAK in a warm-blooded animal in need of such treatment. For example, Form A of the present invention can be used to inhibit JAK kinases in vivo as a therapeutic approach for treating or preventing diseases partially or fully mediated by JAK kinase activity (referred to herein as JAK kinase-mediated diseases). Non-limiting examples of JAK kinase-mediated diseases that may be treated or prevented include the treatment of obstructive, restrictive or inflammatory airway disease of any type, etiology or pathogenesis, in particular obstructive, restrictive or inflammatory airway disease, including as as above, asthma, in particular atopic asthma, allergic asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, emphysematous asthma, exercise-induced asthma, emotional-induced asthma, acquired asthma caused by environmental factors, infectious asthma associated with bacterial, fungal, protozoal and/or viral infection, bronchiolitis, cough variant of asthma, drug-induced asthma, etc., rhinitis or sinusitis with various etiologies, including without limitation seasonal allergic rhinitis, year-round allergic rhinitis, vasomotor rhinitis, sinusitis, including acute, chronic sinusitis, ethmoiditis, sinusitis or spheroidal sinusitis; chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COLD), chronic obstructive airway disease (COAD) or small airway obstruction, including without limitation chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis obliterans; bronchitis, including, in particular, acute bronchitis, acute laryngeal-tracheal bronchitis, chronic bronchitis, dry bronchitis, productive bronchitis, infectious asthmatic bronchitis, staphylococcal or streptococcal bronchitis and vesicular bronchitis.

Accordingly, in one aspect of the present invention, methods are disclosed for treating JAK kinase-mediated diseases in a subject in need thereof, comprising administering to the subject an effective amount of a xinafoate salt of a compound of formula (Ia) or an effective amount of Form A. Also disclosed are methods for treating JAK kinase-mediated diseases. in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable composition containing an effective amount of a compound of formula (Ia) or an effective amount of Form A.

In one aspect, a xinafoate salt of a compound of formula (Ia) is also disclosed for use in the treatment of JAK kinase-mediated diseases in a subject in need thereof. In another aspect, pharmaceutically acceptable compositions containing a xinafoate salt of a compound of formula (Ia) are disclosed for use in the treatment of JAK kinase-mediated diseases in a subject in need thereof. In one aspect, also disclosed herein is Form A for use in the treatment of JAK kinase-mediated diseases in a subject in need thereof. In another aspect, pharmaceutically acceptable compositions containing Form A are disclosed for use in the treatment of JAK kinase-mediated diseases in a subject in need thereof.

In one aspect, the use of a xinafoate salt of a compound of formula (Ia) in the manufacture of a medicament for use in the treatment of JAK kinase-mediated diseases in a subject in need thereof is also disclosed. In one aspect, the use of Form A in the manufacture of a medicament for use in the treatment of JAK kinase-mediated diseases in a subject in need thereof is also disclosed.

In one aspect, the present invention discloses methods of treating asthma in a subject in need thereof, comprising administering to the subject an effective amount of a xinafoate salt of a compound of formula (Ia) or an effective amount of Form A. Also disclosed are methods of treating asthma in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable composition containing an effective amount of a xinafoate salt of a compound of formula (Ia) or an effective amount of Form A.

In one aspect, a xinafoate salt of a compound of formula (Ia) is also disclosed for use in the treatment of asthma in a subject in need thereof. In another aspect, pharmaceutically acceptable compositions are disclosed containing the xinafoate salt of a compound of formula (Ia) for use in the treatment of asthma in a subject in need thereof. In one aspect, Form A is also disclosed for use in the treatment of asthma in a subject in need thereof. In another aspect, pharmaceutically acceptable compositions containing Form A are disclosed for use in the treatment of asthma in a subject in need thereof.

In one aspect, the use of a xinafoate salt of a compound of formula (Ia) in the manufacture of a medicament for use in the treatment of asthma in a subject in need thereof is also disclosed. In one aspect, the use of Form A in the manufacture of a medicament for use in treating asthma in a subject in need thereof is also disclosed.

Accordingly, in one aspect of the present invention, methods of treating COPD in a subject in need thereof are disclosed, comprising administering to the subject an effective amount of a xinafoate salt of a compound of formula (Ia) or an effective amount of Form A. Also disclosed are methods of treating COPD in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable a composition containing an effective amount of a xinafoate salt of a compound of formula (Ia) or an effective amount of Form A.

In one aspect, a xinafoate salt of a compound of formula (Ia) is also disclosed for use in the treatment of COPD in a subject in need thereof. In another aspect, pharmaceutically acceptable compositions containing the xinafoate salt of a compound of formula (Ia) are disclosed for use in the treatment of COPD in a subject in need thereof. In one aspect, Form A is also disclosed for use in the treatment of COPD in a subject in need thereof. In another aspect, pharmaceutically acceptable compositions containing Form A are disclosed for use in the treatment of COPD in a subject in need thereof.

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In one aspect, the use of a xinafoate salt of a compound of formula (Ia) in the manufacture of a medicament for use in the treatment of COPD in a subject in need thereof is also disclosed.

In one aspect, the use of Form A in the manufacture of a medicament for use in the treatment of COPD in a subject in need thereof is also disclosed.

Examples

The present invention is further illustrated by the following examples, which are intended to illustrate several embodiments of the present invention. Such examples are not intended and should not be construed as limiting the scope of the present invention. It will be understood that the present invention may be practiced in a manner different from that specifically described herein. Numerous modifications and variations of the present invention are possible in view of the teachings set forth herein and, therefore, are within the scope of the present invention.

The present inventors have discovered that the new salts of formula (I) have advantageous properties over, for example, compounds of formula (I) in free base form. For example, the xinafoate salt has favorable mechanical and physicochemical properties (i.e., it is non-hygroscopic).

In examples, unless otherwise noted:

(i) yield values are for illustrative purposes only and are not necessarily the maximum achievable;

(ii) NMR data, when given, are presented in the form of delta values for the main diagnostic protons, given in parts per million (ppm), using perdeuterodimethyl sulfoxide (DMSO-d ₆ ) as the solvent, unless otherwise noted, the following abbreviations have been used : s - singlet; d - doublet; t - triplet; q - quartet; m - multiplet; br - wide;

(iii) chemical symbols have their usual meanings; SI units and symbols are used;

(iv) solvent ratios are given in volume:volume (v/v) units;

(v) X-ray powder diffraction analysis was performed as described in the Examples;

(vi) in the examples below, the number of moles and yields reported are based on the starting materials and reactants being 100% w/w, thereby taking into account the purity of the materials used.

Example 1.

Intermediate 1: 7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl1H-indole

Stage 1.

Add a solution of NaOH (599 g, 14986.55 mmol) in water (1500 ml) to a stirred mixture of 7-nitro-N-indole (243 g, 1498.65 mmol) and tetrabutylammonium hydrogen sulfate (50.9 g, 149.87 mmol) in DCM (3000 ml) at 25°C for a period of 5 minutes under air. The resulting mixture was stirred at 25°C for 20 minutes. 4-Methylphenylsulfonyl chloride (371 g, 1948.25 mmol) was added under air and the resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with DCM (2000 ml) and washed successively with water (2x500 ml), 10% aqueous K2CO3 (2x500 ml) and 1 M HCl (2x500 ml), and saturated NaCl solution (2x500 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. When approximately 200 mL of DCM remained, EtOAc (500 mL) was added. The solvent was removed under reduced pressure. When approximately 200 ml of EtOAc remained, MTBE (1000 ml) was added. The precipitate was collected by filtration, washed with MTBE (1000 ml) and dried under vacuum to obtain 7-nitro-1tosyl-1H-indole (402 g, 85%) as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.39 (s, 3H), 7.09 (d, 1H), 7.40-7.55 (m, 3H), 7.75-7, 85 (m, 3H), 7.958.00 (m, 1H), 8.06 (d, 1H);

mass/charge (ES+), [M+H]+=317.

Stage 2.

Bromine (81 ml, 1580 mmol) was added dropwise to 7-nitro-1-tosyl-III-indole (50 g, 158 mmol) in CCl ₄ (1000 ml) at 80°C. The resulting solution was stirred at 80°C for 6 hours. The mixture was cooled to room temperature, concentrated in vacuo, and the residue was washed with EtOAc to give 3-bromo-7-nitro-1-tosyl-1H-indole (53 g, 85 %) as a brown solid.

1H NMR (300 MHz, DMSO-d6) δ 2.41 (s, 3H), 7.55-7.62 (m, 2H), 7.57 (t, 1H), 7.85-7.92 ( m, 3H), 7.96 (d, 1H), 8.49 (s, 1H);

mass/charge (ES-), [M-N] ⁺ =393.

Stage 3.

Solution of 3-bromo-7-nitro-1-tosyl-1H-indole (200 g, 506 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2' bi(1,3,2-dioxaborolane) (193 g, 759 mmol), potassium acetate (99 g, 1012 mmol) and PdCl ₂ (dppf) (18.5 g, 25.3 mmol) in 1,4-dioxane (1500 ml) was degassed three times with nitrogen and the reaction mixture was stirred at 90°C for 8 hours. The mixture was cooled to room temperature and concentrated in vacuo. The solid was treated with water, filtered, washed with methanol and dried in vacuo to give 7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H -indole (150 g,

67%) as a gray solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 1.41 (s, 12H), 2.47 (s, 3H), 7.38-7.43 (m, 3H), 7.66 (d, 1H) , 7.87 (d, 2H), 8.24 (s, 1H), 8.29-8.32 (d, 1H). mass/charge (ES+), [M+H]+=443.

Intermediate 5: 2-fluoro-3-(methylsulfonyl)aniline

Stage 1.

Copper(T) iodide (1.002 g, 5.26 mmol) was added in one portion to 3-bromo-2-fluoroaniline (5 g, 26.31 mmol), N1,N2-dimethylethane-1,2-diamine (0.464 g, 5.26 mmol) and sodium iodide (7.89 g, 52.63 mmol) in 1,4-dioxane (10 ml) at 25°C for a period of 1 minute under nitrogen atmosphere. The resulting suspension was stirred at 110°C for 1 day. The reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using a gradient of 5 to 30% EtOAc in petroleum ether as the mobile phase. The purified fractions were evaporated in vacuo to give 2-fluoro-3-iodoaniline (5.00 g, 80%) as a brown oil.

¹ H NMR (400 MHz, DMSO-d6) δ 5.32 (bs, 2H), 6.59-6.83 (m, 2H), 6.83-6.93 (m, 1H);

mass/charge (ES+), [M+H]+=238.

Stage 2.

Add copper(I) iodide (0.402 g, 2.11 mmol) to 2-fluoro-3-iodoaniline (5.00 g, 21.10 mmol), sodium methanesulfinate (3.23 g, 31.64 mmol), K1 ,N-dimethylethane-1,2-diamine (0.558 g, 6.33 mmol) in DMSO (20 ml) under nitrogen. The resulting suspension was stirred at 95°C for 18 hours. The reaction mixture was diluted with EtOAc (50 ml), washed with water (50 ml) and brine (50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by preparative TLC using EtOAc/petroleum ether 1:1 to give 2-fluoro-3(methylsulfonyl)aniline (3.20 g, 80%) as a colorless oil which solidified on standing.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.20 (s, 3H), 3.96 (bs, 2H), 6.97-7.13 (m, 2H), 7.20-7.31 ( m, 1H);

mass/charge (ES+), [M+H]+=190.

Intermediate 18: 3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin4-yl)-1H-indol-7-amine

Stage 1.

A 1 L reactor equipped with a thermometer and nitrogen inlet was charged with potassium carbonate solution (40.9 mL, 678.28 mmol). The mixture was degassed three times with N2 at room temperature (23°C). 7-Nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl1H-indole, intermediate 1 (100 g, 226.09 mmol) was added. 2,4-dichloro-5-fluoropyrimidine (49.1 g, 293.92 mmol) and methyl THF (1000 ml), and stirred for 10 min at room temperature. The resulting mixture was degassed with nitrogen 3 times. Dichloro[1,1'bis(diphenylphosphino)ferrocene]palladium-dichloromethane adduct (9.23 g, 11.30 mmol) was added to the reaction mixture and the resulting mixture was degassed, refilled (3xN ₂ ) and stirred at 23°C for overnight, producing a yellow precipitate. Heptane (500 ml) was added to the reaction mixture at room temperature and stirred for 10 minutes. Then stirring was stopped and sedimentation was allowed to settle. The reaction mixture was cooled to 5°C and stirred for 1 hour. The precipitate was filtered through a glass funnel, washed with water until the water reached a neutral pH (13 vol., washing by displacement, 1.3 l). The filter cake was then washed with EtOAc/heptane 1:1 (5x2 vol, 1L) at room temperature, heptane (2x200 ml, 2x2 vol) and the solid was dried under vacuum at 35°C overnight to give 3-( 2-chloro-5-fluoropyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole (97 g, actual yield 89%).

^1H NMR (400 MHz, DMSO-d6) δ 2.41 (s, 3H), 7.51 (d, 2H), 7.69 (t, 1H), 7.95 (d, 2H), 8. 01 (dd, 1H), 8.75 (d, 1H), 8.81 (dd, 1H), 9.01 (d, 1H). mass/charge (ES+), [M+H]+=447.2.

Stage 2.

Added 3-(2-chloro-5-fluoropyrimidin-4-yl)-7-nitro-1-tosyl-III-indole (89.5 g, 200.30 mmol), 2-fluoro-3-(methylsulfonyl) hydrochloride aniline, intermediate 5 (54.2 g, 240.36 mmol), Pd ₂ (dba) ₃ (9.17 g, 10.01 mmol) and 2'-(dicyclohexylphosphino)-N,N-dimethyl-[1 ,1'-biphenyl]-2-amine (7.88 g, 20.03 mmol) into a 2 L reactor under nitrogen atmosphere. Degassed 2-2methyltetrahydrofuran (1000 ml) and a solution of cesium carbonate (137 g, 420.62 mmol) in water (450 ml) were added at room temperature and the reaction mixture was degassed (x7). The reaction mixture was then heated to 72.6°C and then stirred overnight.

The reaction mixture was cooled to 4-5°C and stirred for at least 30 minutes. The solid was filtered on a Buchner funnel, washed with cold 2-2-methyltetrahydrofuran (300 ml, 3 vol), water (3 x 300 ml, 3 vol) and EtOAc/heptane 1:2 (3 x 300 ml, 3 vol) and dried under vacuum at 40°C to obtain 5-fluoro-M-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1-tosyl-1H-indol3-yl)pyrimidin- 2-amine (77.89 g, 65% actual yield) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ 2.56-2.64 (m, 3H), 3.42 (d, 3H), 7.52-7.64 (m, 4H), 7.73 ( t, 1H), 7.988.09 (m, 3H), 8.22 (t, 1H), 8.71 (s, 1H), 8.79 (d, 1H), 8.94 (d, 1H), 9.89(s, 1H);

mass/charge (ES+), [M+H] ⁺ =6о0.2.

Stage 3.

5-fluoro-M-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1-tosyl-1H-indol-3-yl)pyrimidin-2-amine (97.7 g, 129.87 mmol) into a 5 L reactor at room temperature. A mixture of THF (100 ml) and 3.8 M NaOH (aq) (1000 ml) was added to obtain a brown insoluble mixture. The mixture was refluxed to 75°C and stirred over the weekend. THF (10 vol.) and heptane (10 vol.) were loaded into the reaction mixture. It was then cooled to 17° C. over 40 minutes, stirred for 60 minutes and the solid was filtered on a Buchner funnel. The filter cake was washed with 1 M citric acid (500 ml, until neutral pH), water (5 x 300 ml, until neutral pH) followed by heptane/EtOAc (4 x 400 ml). The solid was dried under vacuum to give 5-fluoro-M-(2-fluoro-3(methylsulfonyl)phenyl)-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine (55.0 g , 95%).

1H NMR (400 MHz, DMSO- _d6 ) δ 3.27-3.38 (m, 3H), 7.30 (t, 1H), 7.47 (t, 1H), 7.64 (t, 1H ), 8.11-8.29 (m, 3H), 8.52 (d, 1H), 8.98 (d, 1H), 9.60 (s, 1H), 12.57 (s, 1H) ;

mass/charge (ES+), [M+H]+=446.2.

Stage 4.

Into a stirred suspension of 5-fluoro-N-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1H-indol3-yl)pyrimidin-2-amine (59.5 g, 123.5 mmol , 92.5% by weight) in a mixture of THF/EtOH 2:1 (600 ml) at room temperature and under nitrogen atmosphere was added 10% Pd/C (12.0 g, 123.5 mmol, 50% hum.) and a solution of ammonium formate (46.8 g, 741.4 mmol) in water (50 ml). The reaction mixture was slowly heated to 70°C and stirred for 30 minutes. 12 g of activated carbon was added and the mixture was stirred for 15 minutes. The reaction mixture was cooled to 40°C and filtered on a Buchner funnel (paper) under a nitrogen atmosphere. The filter cake was washed with THF/EtOH (160 ml). The filtrate was concentrated to 4 vol., and the resulting suspension was cooled to room temperature and filtered under a nitrogen atmosphere. The solid was washed with water (2 vol), ethanol (2 vol) and dried under nitrogen/vacuo at 40°C to give 3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl) phenyl)amino)pyrimidin-4yl)-1H-indol-7-amine (44.3 g, 86%) as a light brown solid.

^1H NMR (400 MHz, DMSO-d6) δ 3.28 (s, 3H), 5.20 (bs, 2H), 6.43 (dd, 1H), 6.78 (t, 1H), 7. 44 (t, 1H), 7.577.63 (m, 1H), 7.66 (d, 1H), 8.09-8.25 (m, 2H), 8.38 (d, 1H), 9.34 (s, 1H), 11.57 (s, 1H); mass/charge (ES+), [M+H]+=416.3.

Intermediate 28: Methyl 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate

Suspend 1-methylpiperazine (100 g, 988.4 mmol) and potassium carbonate (164 g, 1186 mmol) in dry acetonitrile (800 ml) under a nitrogen atmosphere. Methyl 2-bromo-3-methoxypropanoate (201 g, 988.4 mmol) was added to the slurry at 50-60° C. over a period of 40 minutes. The resulting mixture was heated under a nitrogen atmosphere at 61°C for 23 hours and then cooled to 20°C. The solid was filtered off. The filtrate was evaporated to obtain an oily residue, which was dissolved in 1 M HCl (1000 ml). The pH was then adjusted to 1 with 4 M HCl (~300 mL). The resulting solution was extracted with DCM (200 ml). Increase the basicity of the aqueous solution with saturated Na ₂ CO ₃ solution (1000 ml) until pH 9 and extracted with DCM (2x500 ml). The pH of the aqueous phase was then raised to 10-11 with sodium hydroxide and the result was extracted with DCM (2x500 ml). The four organic phases were combined and evaporated in vacuo to give methyl 3methoxy-2-(4-methylpiperazin-1-yl)propanoate (181 g, 85%).

1H NMR (400 MHz, CDCl·,) δ 2.07 (s, 3H), 2.14-2.34 (m, 4H), 2.39-2.52 (m, 4H), 3.14 ( s, 3H), 3.22 (dd, 1H), 3.42 (dd, 1H), 3.48-3.56 (m, 4H).

Intermediate 48: Lithium 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate

Add a solution of lithium hydroxide (0.321 g, 13.39 mmol) in water (5 ml) to a solution of methyl 3methoxy-2-(4-methylpiperazin-1-yl)propanoate, intermediate 28 (1.93 g, 8.92 mmol), in THF (5 ml). A few drops of MeOH were added until the reaction mixture became clear. The reaction mixture was heated at 40°C for 24 hours. Organic substances were evaporated in vacuo. The residue was diluted with water and lyophilized (x3) to obtain lithium 3-methoxy-2-(4-methylpiperazin1-yl)propanoate (1.92 g, 103%) as a solid.

1H NMR (500 MHz, D ₂ O) δ 2.06 (s, 3H), 2.48 (bs, 8H), 2.99 (t, 1H), 3.20 (s, 3H), 3.46 - 3.57 (m, 2H).

Synthesis of the compound of formula (la) in free base form

Dissolved lithium 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate, intermediate 48 (430 mg, 2.06 mmol), 2-(3H-[1,2,3]triazolo[4,5- L]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(U) (785 mg, 2.06 mmol) and DIPEA (1.068 ml, 6.11 mmol) in DMF (10 ml), stirred at room temperature for 5 min and then 3-(5-fluoro-2-((2-fluoro-3- 8 044028 (methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine was added , intermediate 18 (635 mg, 1.53 mmol).

The reaction mixture was stirred at room temperature for 2 hours, then diluted with DCM (75 ml) and 5% Na ₂ CO ₃ (aq) (50 ml), shaken and the phases were separated. The aqueous phase was extracted with DCM (2x50 ml). The combined organic phases were dried using a phase separator, filtered and evaporated in vacuo. The compound was purified by preparative HPLC on an XBridge C18 column (10 µm, 250x50 mm) using a gradient of 15 to 65% acetonitrile in H2O/ACN/NH3 95/5/0.2 buffer over 20 min at a flow rate of 100 ml/ min. Compounds were detected by UV at 220 nm. The products corresponding to the peaks were collected and lyophilized. The resultant was then crystallized from acetonitrile and the solid was collected by filtration, washed with a minimal amount of acetonitrile and dried in vacuo.

Enantiomers were separated by chiral SFC on a CelluCoat column (250x30 mm, 5 µm) using 25% IPA/DEA 100:0.5 in CO2 at 150 bar with a flow rate of 140 ml/min. Enantiomers were detected by UV at 270 nm. The first eluted enantiomer was collected and lyophilized to give N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1Hindol-7-yl)-3 -methoxy-2-(4-methylpiperazin-1-yl)propanamide.

The second eluted enantiomer was collected and lyophilized. The residue was recrystallized by stirring the suspension in EtOH/water (3:1) (5 ml), heated to 70°C using an oil bath and added seed. The oil bath temperature was then set to 23° C. and the suspension was allowed to slowly cool to room temperature. Stirring was continued for 5 days to obtain a milky slurry containing short needle-shaped crystals with long needle-shaped crystals mixed in. The suspension was heated to 70°C with stirring, then heating and stirring was stopped and the mixture was allowed to slowly cool to room temperature (2x). Only thin, long, needle-shaped crystals remained. The suspension was allowed to settle for more than a week without stirring. The solid was filtered and dried in vacuo at 40°C to give (R)-N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonyl)phenylamino)pyrimidin-4-yl)-1H- indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1 -yl)propanamide (186 mg, 20%, ee 99.4%) as white needle-shaped crystals.

1H NMR (500 MHz, DMSO- _d6 ) δ 2.14 (s, 3H), 2.23-2.45 (m, 4H), 2.57-2.67 (m, 2H), 2.69 -2.78 (m, 2H), 3.26-3.34 (m, 6H), 3.50 (t, 1H), 3.67 (dd, 1H), 3.79 (dd, 1H), 7.03 (t, 1H), 7.4-7.55 (m, 2H), 7.62 (t, 1H), 8.138.33 (m, 3H), 8.44 (d, 1H), 9 .46 (s, 1H), 9.84 (s, 1H), 11.48 (s, 1H).

¹⁹ F NMR (470 MHz, DMSO-d ₆ ) δ -120.52, -147.75; mass/charge (ES+), [M+H]+=600.5.

Synthesis of xinafoate salt of formula (Ia)

(R)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1Nindol-7-yl)-3-methoxy- 2-(4-methylpiperazin-1-yl)propanamide (345 g, 563.82 mmol) into a 10 L reactor with ethyl acetate (20 vol) (7 L) and methanol (4 vol) (1.4 L) (SM solution). The jacket temperature was set to 65°C. Dissolve 1-hydroxy-2-naphthoic acid (106 g, 563.82 mmol) in methanol (1.5 vol) (0.7 L) and ethyl acetate (1.5 vol) (0.7 L) in the reactor volume 2 l and heated to 50°C. The xinafoic acid solution was further filtered through Celite to remove insolubles and washed with EtOAc/MeOH (2:1, 150 ml). The SM solution was further filtered through a celite filter, and the SM crystallized in the receiving vessel due to cooling, but not in the filter. The filtration time was 30 min for ~9 L. The SM suspension was re-charged into the reactor and heated to 65°C to re-dissolve. The xinafoic acid solution was added to a 20 L reactor with the jacket temperature set at 70°C. The solution (SM solution + xinafoic acid solution) was seeded with crystalline material (R)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidine-4- yl)-1H-indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide, and crystallization began immediately. A nitrogen air stream was passed through the headspace into the condenser to remove MeOH. Ethyl acetate (2 L) was added over 5 min to compensate for the loss of azeotrope and ~3 L was distilled. The distillation was completed (5 liters were collected). The cooling process began with a linear temperature change. From 75 to 10°C for 600 min, then kept at 10°C. The solid was filtered using a Schott funnel R3. Filtration was very fast. The solid was washed using an ethyl acetate reactor (2 L) and left to dry in a funnel under nitrogen. The solid was transferred to a drying vessel and dried in a vacuum oven at 40°C.

Initial weight: 426 g.

(4-{(2R)-1-[(3-{5-Fluoro-2-[2-fluoro-3-(methanesulfonyl)anilino]pyrimidin-4-yl}-1H-indol-7yl)amino]-3 -methoxy-1-oxopropan-2-yl}-1-methylpiperazin-1-ium 1-hydroxynaphthalene-2-carboxylate (420 g, 95%) was obtained as an off-white crystalline solid.

1H NMR (400 MHz, DMSO) δ 0.97 (s, 0H), 1.78 (s, 0H), 2.29 (s, 3H), 2.58-3.03 (m, 8H), 3 .09 (s, 7H), 3.37-3.72 (m, 3H), 3.83 (s, 0H), 6.69-6.97 (m, 2H), 7.11-7.36 (m, 4H), 7.42 (s, 1H), 7.54 (t, 2H), 7.86-8.16 (m, 4H), 8.24 (s, 1H), 9.26 ( s, 1H), 9.86 (s, 1H), 11.52 (s, 1H).

- 9 044028

For XRPD, the sample was mounted on a single silicon crystal (SSC) substrate and powder X-ray diffraction was recorded using a Theta-Theta Bruker D8 Advance (X-ray wavelength 1.5418 A, Ni-filtered Cu emission, voltage 40 kV, filament emission 40 mA). A 2.5° Soller slit and a 3 mm anti-scattering slit were used, and the samples were rotated during measurement. Samples were scanned over a 2-theta angle range of 2-50° using a step width of 0.02° and a measurement time per step of 0.04° s ^-1 using a LynxEye 3° PSD detector (10.5 mm detector slit).

Table 1. Positions (°2θ) and intensity values of XRPD peaks

The following definitions were used for relative intensity (%): 25-100%, vs (very strong); 10-25%, s (strong); 3-10%, m (average); 1-3%, w (weak)._________________________

Angle 2-theta (°20) Relative intensity 8.2 w 8.9 w AND 2 w 14.2 w 15.0 S 15.3 S 16.2 S 17.5 w 21.0 S 22.6 S 23.0 w 23.7 w 24.6 w 26.2 w

Example 2.

Based on the crystal structure (obtained using single crystal x-ray diffraction, SXRD) of the compound of formula (Ia) in free base form, the form was determined to be a non-stoichiometric hydrate. This was also further confirmed by gravimetric vapor sorption (GVS) analysis as the water uptake was 2% w/w. observed at 0-80% relative humidity and the compound exhibited a weight loss of 5% w/w. at temperatures from room temperature (RT) to 120°C.

Accordingly, salt screening was carried out and from the 20 counterions tested, three salts (phosphoric, sulfuric and xinafoic acid salts) were weighted (5 g) and further analyzed. Phosphoric and sulfuric acid salts showed a lower degree of crystallinity compared to the xinafoic acid salt and also showed a weight loss of 3.2% w/w. at temperatures ranging from room temperature up to 120°C (sulfuric acid salt) and 5.4% w/w. at temperatures ranging from room temperature up to 120°C (phosphoric acid salt). Gravimetric sorption analysis was not performed for these two salts because they showed such unacceptable solid state properties compared to xinafoate, while having properties similar to or inferior to those of the free base.

The crystal structure (based on SXRD) of the xinafoate salt showed that the salt was a 1:1 salt which was not a non-stoichiometric hydrate but was the anhydrous free base form of the compound of formula (Ia). The simulated powder X-ray diffraction pattern obtained by SXRD was superimposed on experimental powder X-ray diffraction (PXRD) data, indicating that the structure of the single crystal was the same as that in the bulk.

Independent polymorph screening revealed that the non-stoichiometric hydrate of the compound of formula (Ia) in the free base form is the most stable form identified under ambient conditions and that the chances of obtaining an anhydrous free form should be considered very low. Screening was performed on Almac, including over 110 solvent-based and solvent-free screening experiments. The xinafoate salt was found to be a non-hygroscopic form of the compound of formula (Ia), exhibiting an absorption of 0.2% w/w. at 0-80% relative humidity and exhibiting a weight loss of 0.2% w/w. when heating the compound to a temperature ranging from room temperature to 120° C., while the compound of formula (Ia) in free base form was found to be slightly hygroscopic, exhibiting an absorption of 1.7% w/w . at 0-80% relative humidity and exhibiting a weight loss of 5% w/w. at temperatures from room temperature (RT) to 120°C.

Form Water absorption at rel. wet 0-80% (% w/w) Compound of formula (1a) in free base form ~1.7 Xinafoate salt of the compound of formula (1a) ~0.2 Phosphoric acid salt of the compound of formula (1a) No data Sulfate salt of the compound of formula (1a) No data

Weight loss in the range from b.t. to 120°C (% w/w) Degree of crystallinity according to PXRD ~5 High degree of crystallinity ~0.2 High degree of crystallinity ~5.4 Low degree of crystallinity ~3.2 Low degree of crystallinity

Example 3.

An alternative route for the synthesis of the xinafoate salt of formula (Ia) is further described below.

2

Stage 1. 2-Fluoro-3-(methylsulfonyl)aniline (2)

2-fluoro-3-bromoaniline (1), 930 g, 1 eq., 4.9 mol and sodium methanesulfinate, 3 eq., 1.5 kg, followed by DMSO, 5 L, were added to the inerted reactor. The contents of the reactor were inerted 5 times and stirred for 30 minutes at 20-30°C. Copper(I) iodide, 0.2 equiv., 187 g and 1,2-dimethylethylenediamine, 0.4 equiv., 173 g were added to the reactor, which was then inerted 3 times. The reaction mixture was stirred at 110-120°C for 17 hours before it was considered ready for processing. The mixture was cooled to 20-30°C and water 10 l was added, then ethyl acetate 10 l. The mixture was stirred for 30 min and the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (2x10 L). The combined organic layers were evaporated to dryness and dissolved in 2 L of ethyl acetate. The crude product solution was filtered through a short silica column and the column was washed with 10 L of ethyl acetate/petroleum ether 1:1. The eluate was then concentrated to 2 L. Heptane, 1 L, was slowly added to this solution over 2 hours at 20-30°C. The precipitated product was filtered and dried at 40-50°C under reduced pressure to obtain 0.6 kg, 65% of the desired product.

Step 2. 7-Nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (4)

3-bromo-7-nitro-1-(p-tolylsulfonyl)indole (3), 1.2 kg, 3 mol, and bis(pinacolato)diborane, 1.14 kg, 4.5 mol, 1 were added to the inerted reactor .5 eq., then potassium acetate, 590 g, 6 mol, 2 eq. The reactor contents were then inerted and 8.4 L of 1,4-dioxane were charged. The reactor was inertized 3 times, then Pd(PPh ₃ ) ₄ , 0.01 eq., 35 g was added. The reaction mixture was heated to 95-100°C and stirred for 18 hours. A sample was taken for HPLC and the mixture was cooled to 20- 30°C. 2-Methyl-THF, 8.4 L and 8.4 L of water were added to the reaction mixture, which was then stirred for 30 minutes. The organic layer was separated and washed three times with 8.4 L of 10% sodium chloride (aq). The organic solution was evaporated to dryness and evaporation was carried out together with 6 liters of acetonitrile. Finally, 6 L of acetonitrile were added and the mixture was stirred at 20-30°C for 2 hours, then cooled to 0-5°C and stirred for 2 hours, then filtered. The filtered product was dried at 40-50°C under reduced pressure to obtain 1 kg (75%) of the desired product (4).

Step 3 3-(2-Chloro-5-fluoropyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole (6)

7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 was added to the inerted reactor

- 11 044028 tosyl-1H-indole, (4), 1 kg, 2.26 mol, and 2,4-dichloro-5-fluoropyrimidine (5), 442 g, 1.2 eq., then 4 L 2MeTHF. A solution of potassium carbonate, 937 g (3 eq.), in 2 liters of water was charged into the reactor, which was then inerted 5 times. Pd(dppf)Cl ₂ -DCM catalyst, 92 g, 0.05 equiv (113 mmol), was added to the reactor, which was then inertized 3 times, and the mixture was stirred at 20-30°C for 17 hours. A sample was taken for LCMS and added 4 L of n-heptane to the reactor for 2 hours at 20-30°C. The precipitate was stirred for an additional 30 minutes before the product was filtered off and washed with 7 L of water until the filtrate reached a neutral value (pH 7-8). The wet filter cake was obtained as a suspension in ethyl acetate, 3 L (3 vol.) and filtered. Finally, the filter cake was washed with 1 L of ethyl acetate and dried at 40-50° C. under reduced pressure to obtain 0.9 kg (89%) of the desired product (6).

Step 4. 5-Fluoro-N-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1-tosyl-1H-indol-3-yl)pyrimidin-2-amine (7)

Pd ₂ (dba) ₃ , 124 g (0.05 eq.) and DavePhos, 106 g (0.1 eq.), then 2-methyltetrahydrofuran 3 L were added to the inerted reactor. The reactor was inertized 3 times and the contents were stirred for 30 minutes at 20-30°C. 3-(2-chloro-5-fluoropyrimidin-4-yl)-7-nitro-1-tosyl-1Hindole (6), 1 equiv., 1.2 kg, 2.7 mol, and 2-fluoro were loaded into the reactor -3-(methylsulfonyl)aniline hydrochloride, (2) 1 eq., 610 g, 2.7 mol, then 2-methyltetrahydrofuran, 3 l. Cesium carbonate, 1.1 eq., 970 g, in water, 2.4 L was then added to the reactor, which was then inerted again 3 times. The reaction mixture was stirred at 75-80°C for 18 hours, after which the reaction was considered complete. The reaction mixture was cooled to 20-30°C and the precipitated product was filtered off. The filter cake was washed with 2methyltetrahydrofuran, 5 L, then with water, 5 L, and finally with acetone, 5 L. The product was dried at 4050°C under reduced pressure to obtain 1.3 kg of the desired product (7) (80%).

^1H NMR (400 MHz, DMSO) δ 2.40 (s, 3H), 3.32 (s, 3H), 7.43-7.54 (m, 4H), 7.65 (t, 1H), 7.93 (dd, 3H), 8.13 (t, 1H), 8.57-8.66 (m, 1H), 8.69 (d, 1H), 8.84 (d, 1H), 9 .79 (s, 1H).

Step 5. 5-Fluoro-N-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1H-indol-3-yl)pyrimidin-2amine (8)

5-fluoro-N-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1tosyl-1H-indol-3-yl)pyrimidin-2-amine (7), 1 was added to the inerted reactor .10 kg, 1 eq., 1.84 mol, then THF, 5.5 l. 2.2 L of aq. was added to the reactor. solution of 4 M NaOH, and the resulting mixture was stirred at 65-70°C for 45 hours, after which complete hydrolysis was achieved. MTBE, 6.6 L, was added over 3 hours with stirring at 1525°C, resulting in a fine precipitate. The mixture was filtered, and the filter cake was washed with water until neutrality was achieved. Finally, the precipitate was washed with methanol, 2.2 L. The desired product was dried at 40-50°C under reduced pressure to obtain 0.70 kg (84%) of the desired product (8).

1H NMR (400 MHz, DMSO) δ 3.33 (s, 3H), 7.30 (t, 1H), 7.47 (t, 1H), 7.64 (ddd, 1H), 8.06-8 .26 (m, 3H), 8.51 (d, 1H), 8.97 (d, 1H), 9.60 (s, 1H), 12.56 (s, 1H).

Step 6. 3-(5-Fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7amine (9)

5-fluoroN-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1H-indol-3-yl)pyrimidin-2 was loaded into an inertized reactor with a volume of 25 l, preheated to 55°C. -amine (8) (578 g, 1.26 mol), then THF, 8.5 L. Ammonium formate (475 g, 7.53 mol) in 2.3 L water was added to the suspension, followed by Pd/C (170 g, 80 mmol Pd) and finally 4.3 L ethanol over 5 min. The final mixture was heated from room temperature to 43°C. The reaction was initiated by the addition of ethanol, which resulted in gas evolution. Within 1 hour the conversion was complete, which was monitored by UPLC-MS. The reaction mixture was hot filtered to remove Pd/C. The reactor was washed with 3 L of a hot 2:1 THF/ethanol mixture (55°C), which was also collected by passing through a filter. The filtrate was evaporated to a semi-solid mixture, which was triturated with 2.5 L of ethanol under nitrogen overnight. The product was filtered and dried at 40°C in vaccuo. Yield: 508 g, analysis 100%. Melting point: 236°C (start of DSC), HRMS (ESI ⁺ ): [M+H] ⁺ mass/charge calc. for C ₁₉ H ₁₅ F ₂ N ₅ O ₂ S 416.0987; The value found is 416.0996.

1H NMR (400 MHz, DMSO) δ 3.29 (s, 3H), 5.20 (s, 2H), 6.44 (d, 1H), 6.79 (t, 1H), 7.45 (t , 1H), 7.56-7.75 (m, 2H), 8.08-8.25 (m, 2H), 8.39 (d, 1H), 9.35 (s, 1H), 11, 58 (s, 1H).

¹⁹ F NMR (376 MHz, DMSO) δ -147.61, -120.58.

- 12 044028

Step 7. Methyl 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate (10)

Potassium carbonate, 396 g, 1.3 eq., was then added to a glass reactor under nitrogen atmosphere, followed by 1.8 L of dry acetonitrile, Sigma-Aldrich 34851N (0.004% water) and 1-methylpiperazine, 99%, 234 g, 2.3 eq. mol, 1.05 eq. The jacket temperature was set to 60°C. To the resulting suspension was added methyl 2-bromo-3methoxypropanoate, 448 g, 97%. 2.2 mol, 300 ml in 200 ml dry acetonitrile at 60°C for 1 hour, maintaining the reaction temperature below the boiling point. After 19 hours, NMR showed that the conversion was 99%. The reaction was completed after 24 hours. The reactor contents were filtered through a celite plate filter. The filter cake was washed with 500 ml of acetonitrile and the combined organic layers were evaporated to an oil. The crude oil product was dissolved in 1 L of isopropyl acetate and extracted with 200 ml of water to remove the salts. The product is highly soluble in water and a backwash with isopropyl acetate is necessary to recover the material (this water wash can be omitted as it requires a lot of extra work resulting in only a small increase in product purity). The combined isopropylacetate extracts were evaporated under reduced pressure at 60°C. This provided the title compound (10) as a yellow oil (471 g, 99% w/w, 98% yield).

¹ H NMR(400 MHz, CDCl ₃ ) δ 2.16 (s, 3H), 2.33 (m, 4H), 2.55 (m, 4H), 3.23 (s, 3H), 3.31 (dd, 1H), 3.51 (dd, 1H), 3.60 (dd, 1H), 3.61 (s, 3H).

¹³ C NMR (101 MHz, CDCl3) δ 45.97, 50.01, 51.32, 55.20, 59.09, 67.03, 70.71, 170.85. HRMS (ESI ⁺ ): [M+H] ⁺ mass/charge calc. for C ₁₀ H ₂₁ N ₂ O ₃ 217.1552;

The value found is 217.1547.

Step 8. Lithium 3-Methoxy-2-(4-methylpiperazin-1-yl)propanoate (11)

_In a 5-liter reactor under a nitrogen atmosphere, a solution of methyl-3-methoxy-2-(4-methylpiperazine-1- yl)propanoate (441 g, 2000 mmol) in 1 L THF and 300 ml methanol. The reaction mixture was heated at 40°C for 72 hours, after which it was determined by NMR that the transformation was complete. The reaction mixture was evaporated to an oil, which solidified into a foam after drying in vaccuo at 40°C to give the title compound (11) (435 g, 97% w/w, 93% yield).

1H NMR(400 MHz, CDCl3) δ 2.24 (s,3H), 2.45 (m, 4H), 2.64 (m, 4H), 3.02 (dd, 1H), 3.63 (dd , 1H), 3.72 (dd, 1H).

¹³ C NMR (101 MHz, DMSO) δ 45.9, 49.76, 55.01, 57.91, 70.18, 72.18. HRMS (ESI ⁺ ): [Macid+H] ⁺ mass/charge calc. for C9H ₁₉ N ₂ O ₃ 203.1396; The value found is 203.1388.

Stage 9. Chromatography

Enantiomers of 11 (180 g, 865 mmol) were separated by chiral supercritical fluid chromatography using Lux Cellulose-4 (5 μm, 250x50 mm) with a mobile phase of 25% MeOH/NH ₃ 100/0.5 in CO ₂ at 120 bar, at 30°C, with a flow rate of 420 g/min and detection at 215 nm. The second eluted compound was collected and evaporated to give (K)-3-methoxy-2-(4methylpiperazin-1-yl)propanoic acid of the title compound (80 g, 99.6% ee).

Stage 9a. Salt separation

L-(+)-Tartrate salt of (K)-3-methoxy-2-(4-methylpiperazin-1-yl)propanoic acid

Under a nitrogen atmosphere in a stirred reactor, lithium 3-methoxy-2-(4-methylpiperazin-1yl)propanoate, 208 g, 1 mol, was dissolved in 625 ml distilled water, and the pH was adjusted to 4 with 3.8 M HCl, 340 ml. The temperature increased from room temperature to 33°C. L-(+)-Tartaric acid, 145 g, 0.97 mol, was dissolved in 170 ml distilled water and added to the previous solution, then 300 ml ethanol (99.5% w/w) was added. Crystallization could be induced by seeding, but stirring overnight at room temperature (20-21°C) also initiated crystallization. Before filtration, 200 ml of ethanol (99.5% w/w) was slowly added, the reaction mixture was cooled to 10°C and stirring was continued for 1 hour. The product was filtered and washed with 300 ml of cold ethanol (99.5% w/w ./weight.). The collected product crystals were dried in

- 13 044028 vaccuo at 40°C for 72 hours. The yield was 144 g, Mw = 388.37 (2 molecules of crystalline water in accordance with X-ray structural analysis of the crystal), 0.37 mol, 74%. Melting point:

139°C (peak, DSC). ^1H NMR (400 MHz, D2O) δ 2.98 (s,3H), δ 2.84 (s,3H), δ 3.45-3.71 (m, 8H), δ 3.84 (t, 1H), δ

3.92 (dd, 2H), δ 4.53 (s, 4H), δ 4.79 (s, 4H) + additional water from solvent.

Data regarding the crystal. C ₁₃ H ₂₈ N ₂ O ₁₁ , M _r =388.37, orthorhombic, P2 ₁ 2 ₁ 2 ₁ (No. 19), a=7.1515(4) A, b=13.9607(7) A, s =17.6138(11) A, α=β=γ=90°, V=1758.56(17) A ³ , T=100(2) K, Z=4, T=1, p(CuKa)= 1.109, 10608 measured reflections, 3096 unique (R _mt =0.0898), which were used in all calculations. The final wR ₂ was 0.2209 (all data) and R ₁ was 0.0670 (I>2(I)).

Stage 9b. (R)-3-methoxy-2-(4-methylpiperazin-1-yl)propanoic acid dihydrochloride salt (12) g L-(+)-tartaric acid salt (R)-3-methoxy-2-(4-methylpiperazin- 1-yl)propanoic acid was dissolved in 200 ml of warm distilled water and loaded onto 300 ml of Dowex 50WX2-100 cation exchange resin in a column, approx. 200 g in its H-form (washed with distilled water until neutral). The column was eluted with distilled water (-700 ml, 2-3 column volumes) until it reached neutral pH after addition. The amino acid was then eluted with 2 M HCl, 900 ml (3 column volumes), to give 28 g, 90% (dry weight) HCl salt of the amino acid as an oil, which soon crystallized. Some material could still be on the column because there was no detector connected to the ion exchange device. NMR. Analysis 93%, water content 2.24% (KF). 21 g of product was dissolved in 5 vol. 100 ml of absolute ethanol, heated under reflux (if the material is non-crystalline, 3 vol. is sufficient), and left to cool to ambient temperature. When the crystallization process came to an end, 3 vol. MTBE, 60 ml, was added slowly to reduce the solubility of the salt. The product was filtered and dried at 40°C under reduced pressure for 17 hours. Melting point: 141.6 (DSC, start, 3°C/min). Water content: 6.12% (6.18% for one molecule of crystalline water), NMR analysis, 97.5%. Yield: 70%, 14 g. The salt is soluble in ethanol, making it a non-ideal solvent for recrystallization, but water is added to the salt. The mother liquor contains the missing 30% that can be obtained from it.

¹ H NMR(400 MHz, D2O) δ 2.99 (s, 3H), δ 3.33 (s, 3H), δ 3.53 (t, 2H), δ 3.66 (m, 2H), δ 3.85 (t, 2H), δ 3.96 (m, 1), δ 3.98 (d, 2H), δ 4.32 (t, 1H), δ 4.79 (s, 2H) + additional water from solvent.

Step 10 (R)-N-(3-(5-Fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1Nindol-7-yl)-3-methoxy -2-(4-methylpiperazin-1-yl)propanamide (13)

(R)-3methoxy-2-(4-methylpiperazin-1-yl)propanoic acid, 2HC1 (12) (430 g, 1187.6 mmol), then 3 L of DMF (6 about.). 3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine (9) (449 g) was loaded into the light brown solution , 1079.6 mmol). The resulting dark brown transparent solution was cooled to -20°C (jacket temperature was set to -30°C). Pyridine, 1.3 L, was added to the reactor over 5 minutes. No significant exothermic effect was observed. At -20°C, propanephosphonic anhydride (T3P) in DMF (1.9 L, 3239 mmol) was added very slowly without exceeding -13°C. The jacket temperature was set to -40°C due to the exothermic reaction. The addition was completed after 75 minutes. After 2/3 of the addition procedure, a sample was taken and SFC-MS was performed and almost complete conversion was detected. The complete transformation occurred after the addition procedure was fully implemented. Final UPLC-MS analysis. The reaction mixture was quenched by slowly adding water at -15°C over 1 hour. The quenched mixture was stirred for an additional 30 minutes at -15°C. A larger reactor with 8.5% NaHCO3 (14 L) was prepared in advance and cooled to +5°C to minimize foam formation, while the quenched reaction mixture was transferred slowly to a reactor containing 8.5% _NaHCO3 (14 L), with using a short pressurized tube. After addition for 1 hour, an additional 18 L of saturated bicarbonate solution was added, causing the product to begin to precipitate from the clear solution. The precipitated product mixture was stirred for 30 minutes at +5°C. The crude clay-like product was filtered off. The product was poorly filtered, and the procedure took considerable time. The product was dried at 40°C under reduced pressure for 72 hours. The yield was

Claims (24)

put 665 g with the analyzed 87% (81%). Dry crude material 665 g with an analyzed purity of 87% was loaded into an inertized reactor and 13 l of acetonitrile was added. The mixture was stirred under reflux starting at ambient temperature. Acetonitrile, 2 L, was added to improve the solubility of the product. The opaque solution was filtered until clear, resulting in some degree of crystallization. Filtration was difficult and insoluble material was clogging the filter. There was a need to return the product solution on the filter to the reactor when clogging occurred. Overall, the volume doubled during filtration, which required a lot of time. The organic material, filtered to a transparent state, was transferred to another reactor and the volume was reduced to 13 l. Crystallization was initiated by reflux (clear solution) with slow cooling to 5°C over 24 hours. The product was filtered and washed with 2 vol. cold acetonitrile. The product was dried under reduced pressure overnight at 40°C. Yield: 364 g, 63%, purity 98% (NMR). HRMS (ESI ⁺ ): [M+H] ⁺ mass/charge calc. for C ₂₈ H ₃₁ F ₂ N ₇ O ₄ S 600.2204; The value found is 600.2199. 1H NMR (400 MHz, DMSO) δ 2.14 (s, 3H), 2.35 (s, 4H), 2.55-2.68 (m, 2H), 2.68-2.85 (m, 2H), 3.29 (s, 3H), 3.30 (s, 3H), 3.51 (t, 1H), 3.67 (dd, 1H), 3.79 (dd, 1H), 7, 04 (t, 1H), 7.39-7.57 (m, 2H), 7.62 (td, 1H), 8.118.33 (m, 3H), 8.44 (d, 1H), 9.46 (s, 1H), 9.88 (s, 1H), 11.53 (s, 1H). Step 11. Xinafoate salt (R)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl )-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide (14) (R)-N-(3-(5-Fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl) amino)pyrimidin-4-yl)-1H-indol-7-yl)-3methoxy-2-(4-methylpiperazin-1-yl)propanamide (13) (345 g, 563.82 mmol) was charged into an inertized reactor with a volume of 10 l. At the same time, ethyl acetate (7 l, 20 vol.) and methanol (1.4 l, 4 vol.) were loaded. The mixture was heated to 65°C until all contents were completely dissolved. The solution was additionally filtered while hot through a celite filter. Crystallization occurred in the filtrate. The filtrate suspension was transferred back to the reactor and heated to 60°C until complete redissolution. 1-Hydroxy-2naphthoic acid (106 g, 563.82 mmol) was charged into a 2 L inertized reactor. Methanol (0.7 L, 1.5 vol.) and ethyl acetate (0.7 L, 1.5 vol.) were charged and the mixture was heated to 50°C until all contents were completely dissolved. The solution was further filtered and the filter was washed with EtOAc/MeOH (2:1, 150 ml). The resulting solution was added to a 10 L reactor at 60°C to obtain a clear solution, which was stirred for 10 minutes. A seed in the form of crystalline material (7 g) from the previous batch was introduced into the solution. The initiation of crystallization occurred immediately. The solvent was distilled off at atmospheric pressure and a jacket temperature of 75°C using a nitrogen flow passing through the headspace until the reflux temperature did not exceed 70°C. 5 L of distillate was collected and EtOAc (2 L) was added to the reactor to compensate for volume loss. The reactor was slowly cooled to 10° C. over 10 hours and maintained at this temperature for 4 hours. The solid was filtered and washed using the reactor with ethyl acetate (2 L). The solid was dried under vacuum at 40°C. The xinafoate salt (R)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1Nindol-7-yl)-3- was obtained. methoxy-2-(4-methylpiperazin-1-yl)propanamide (14) (420 g, 95% yield) as an off-white crystalline solid. Purity (NMR): 97.7%. ¹ H NMR (400 MHz, DMSO) % 2.29 (s, 3H), 2.58-3.03 (m, 8H), 3.09 (s, 7H), 3.37-3.72 (m , 3H), 6.69-6.97 (m, 2H), 7.11-7.36 (m, 4H), 7.42 (s, 1H), 7.54 (t, 2H), 7. 86-8.16 (m, 4H), 8.24 (s, 1H), 9.26 (s, 1H), 9.86 (s, 1H), 11.52 (s, 1H). ¹⁹ F NMR (376 MHz, DMSO) δ -147.71, -120.45. Melting point: 189°C (DSC, peak) HRMS (ESI ⁺ ): [M+H] ⁺ mass/charge calc. for C ₂₈ H ₃₁ F ₂ N ₇ O ₄ S 600.2204; The value found is 600.2199 (original). CLAIM 1. Xinafoate salt of formula (Ia) CH ₃ OH 0' formula (1a). 2. Salt according to claim 1, which is in crystalline form. 3. A pharmaceutical composition containing the xinafoate salt according to claim 1 in combination with a pharmaceutically acceptable excipient, diluent or carrier. 4. A pharmaceutical composition comprising the xinafoate salt of claim 2 in combination with a pharmaceutically acceptable excipient, diluent or carrier. 5. Crystalline Form A of the compound of formula (Ia) as defined in claim 1. 6. Crystalline Form A according to claim 5, characterized by a powder X-ray diffraction pattern with specific peaks at 15.0° and 21.0°, and 22.6° (±0.1°). 7. Crystal form A according to claim 5, characterized by a powder X-ray diffraction pattern with specific peaks at 8.2°, 8.9°, 11.2°, 14.2°, 15.0°, 15.3°, 16, 2°, 17.5°, 21.0°, 22.6°, 23.0°, 23.7°, 24.6° and 26.2° (± 0.1°). 8. A method for producing xinafoate salt according to claim 1, including: (i) dissolution of (R)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1Nindol-7-yl)-3 -methoxy-2-(4-methylpiperazin-1-yl)propanamide in a suitable solvent; (ii) dissolving xinafoic acid in a suitable solvent; (iii) mixing the two solutions; (iv) providing crystallization of (4-{(2R)-1-[(3-{5-fluoro-2-[2-fluoro-3-(methanesulfonyl)anilino]pyrimidin-4-yl} - 1H-indol-7 -yl)amino]-3-methoxy-1-oxopropan-2-yl}-1-methylpiperazin1-ium 1-hydroxynaphthalene-2-carboxylate and (v) isolation of (4-{(2R)-1-[(3- {5-fluoro-2-[2-fluoro-3-(methanesulfonyl)anilino]pyrimidin-4-yl}-1Hindol-7-yl)amino]-3-methoxy-1-oxopropan-2-yl} -1 - methylpiperazin-1-ium 1-hydroxynaphthalene-2-carboxylate. 9. The method according to claim 8, including adding seed crystals (4-{(2R)-1-[(3-{5-fluoro-2-[2fluoro-3 -(methanesulfonyl)anilino]pyrimidin-4-yl} - 1 H-indol-7-yl)amino]-3-methoxy-1-oxopropan-2yl}-1-methylpiperazin-1-ium 1-hydroxynaphthalene-2-carboxylate after step (iii). 10. The method according to claim 8, in which (R)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1 H -indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1 -yl)propanamide from step (i) is prepared by reaction between 1-[(III)-1-carboxy-2-methoxyethyl]-4 dichloride -methylpiperazine1,4-diium and 3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine. 11. Use of xinafoate salt according to claim 1 as a medicinal product. 12. A method of treating a JAK kinase-mediated disease in a subject in need thereof, comprising administering to the subject an effective amount of a xinafoate salt of formula (Ia) as defined in claim 1. 13. The method of claim 12, wherein the JAK kinase-mediated disease is asthma or COPD. 14. A method of treating a JAK kinase-mediated disease in a subject in need thereof, comprising administering to the subject an effective amount of Form A of formula (Ia) as defined in any one of claims 5 to 7. 15. The method of claim 14, wherein the JAK kinase-mediated disease is asthma or COPD. 16. Use of the xinafoate salt of claim 1 for the treatment of a JAK kinase-mediated disease in a subject in need thereof. 17. Use according to claim 16, wherein the JAK kinase-mediated disease is asthma or COPD. 18. Use of the xinafoate salt crystal Form A of any one of claims 5 to 7 for the treatment of a JAK kinase-mediated disease in a subject in need thereof. 19. Use according to claim 18, wherein the JAK kinase-mediated disease is asthma or COPD. 20. Use of the xinafoate salt of claim 1 for the manufacture of a medicament for the treatment of a JAK kinase-mediated disease in a subject in need thereof. 21. Use according to claim 20, wherein the JAK kinase-mediated disease is asthma or COPD. 22. Use of the xinafoate salt crystal Form A according to any one of claims 5 to 7 for the manufacture of a medicament for the treatment of a JAK kinase-mediated disease in a subject in need thereof. 23. Use according to claim 22, wherein the JAK kinase-mediated disease is asthma or COPD. 24. Compound representing 4-[(1R)-1-carboxy-2-methoxyethyl]-1methylpiperazin-1-ium (2R,3R)-3-carboxy-2,3-dihydroxypropanoate hydrate (1:1:2) -